The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index; 6 of the 47 sources its claims cite were checked for support.
Crystal structures of a double-barrelled fluoride ion channel
Open accessAbstract
To contend with hazards posed by environmental fluoride, microorganisms export this anion through F(-)-specific ion channels of the Fluc family. Since the recent discovery of Fluc channels, numerous idiosyncratic features of these proteins have been unearthed, including strong selectivity for F(-) over Cl(-) and dual-topology dimeric assembly. To understand the chemical basis for F(-) permeation and how the antiparallel subunits convene to form a F(-)-selective pore, here we solve the crystal structures of two bacterial Fluc homologues in complex with three different monobody inhibitors, with and without F(-) present, to a maximum resolution of 2.1 Å. The structures reveal a surprising 'double-barrelled' channel architecture in which two F(-) ion pathways span the membrane, and the dual-topology arrangement includes a centrally coordinated cation, most likely Na(+). F(-) selectivity is proposed to arise from the very narrow pores and an unusual anion coordination that exploits the quadrupolar edges of conserved phenylalanine rings.
Overview
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Written from the paper’s full text.
TL;DR
Crystal structures of bacterial Fluc homologues Bpe and Ec2 in complex with monobody inhibitors reveal a “double-barrelled” antiparallel homodimer with two narrow F⁻ pathways and a centrally coordinated Na⁺. Mutational and flux assays support key roles for conserved phenylalanines and N43 in F⁻ permeation and selectivity.
Key findings
- Structures solved to a maximum resolution of 2.1 Å show an antiparallel homodimer with a novel fold, a ~1700 Ų membrane-embedded dimer interface, and a central plug containing a Na⁺ coordinated by backbone carbonyls from the conserved TM3 break (G77, T80).
- The Bpe-L2 structure contains four densities provisionally assigned as F⁻ ions in peripheral crevices, suggesting two antiparallel pores rather than a single central pore; Ec2-S9 shows equivalent densities at the F1 positions, with Cα rmsd 0.6 Å between Bpe and Ec2 folds.
- F⁻ selectivity is proposed to arise from very narrow pores and unusual anion coordination involving conserved phenylalanine rings (F82, F85) in side-on/quadrupolar orientation, plus H-bond donors including N43, S108, and S112.
- Anion-dump assays: wild-type Bpe F⁻ efflux is ~3×10⁵ s⁻¹; F85I is 1950 ± 200 s⁻¹ and F82I is 200 ± 12 s⁻¹; N43D efflux is 4330 ± 440 s⁻¹ at pH 6.5, 1860 ± 210 s⁻¹ at pH 7, and undetectable at pH 9.
Methods
- Crystallized Bpe with monobodies S7 and L2, and Ec2 with monobody S9, using detergent micelles or lipidic cubic phase; Bpe-S7 phases were determined by Hg-SAD and improved with Hg/Se-SIRAS, Bpe-L2 by molecular replacement, and Ec2-S9 by Se-SAD.
- Functional measurements used single-channel recording in planar lipid bilayers and electrochemical anion-efflux assays from proteoliposomes loaded with KF or KCl, including Bpe mutants F82I, F85I, and N43D.
- Structural analysis included model building/refinement, sequence alignments of eukaryotic and bacterial Fluc domains, and comparison of conserved pore-lining residues.
Limitations
- The authors state that the low-resolution Bpe-S7 structure lacks F⁻ and does not reveal the ion-permeation pathway; they also state that the evidence for assigning the four densities as F⁻ is not sufficiently strong to accept the double-barrelled picture as firmly established.
- The authors note that monobodies might force a conformation in which the two pores are less open than in the fully conducting state, that Ec2 densities corresponding to F2 cannot be unambiguously assigned, and that the energetic contributions of phenylalanine edge-on coordination have not been established.
- Evident from the text: the double-barrelled architecture is inferred from crystallographic densities and functional mutagenesis rather than a direct open-state structure, and N43S/N43A mutants were biochemically intractable, limiting analysis of that position.
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Claims the paper makes
56 Own result · 23 Own interpretation · 19 Not checked yet · 9 No basis given · 8 Own method · 5 Sources not found · 3 No full text of the sources · 2 Partly supported · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Unicellular organisms directly exposed to environmental F- counteract the anion’s toxicity through the action of F--exporting membrane transport proteins that keep cytoplasmic F- below inhibitory levels1–4,8.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Partly supportedcites [1] Baker, J. L. et al. Widespread genetic switches and toxicity resistance proteins for fluoride. Science 335, 233–235 (2012) sourceExperimental — accuracy not yet measured
The passage discussing Fig. 3 and Fig. 2 reports that CrcB reduces cellular fluoride and its toxicity, while the passage discussing Fig. 3C reports fluoride transport by EriCF. The paper describes CrcB transport as a speculation and does not establish that these proteins export fluoride or keep cytoplasmic levels below an inhibitory threshold; no page numbers are available in our copy. (LLM, conf=0.85)
- Supportedcites [2] Li, S. et al. Eukaryotic resistance to fluoride toxicity mediated by a widespread family of fluoride export proteins. Proc. Natl Acad. Sci. USA 110, 19018–19023 (2013) source
The Discussion states that FEX proteins maintain low intracellular fluoride across multiple domains of life and promote cell survival under fluoride stress. The Results show that removing FEX raises intracellular fluoride and fluoride sensitivity in the unicellular fungi studied. (LLM, conf=0.92)
- Supportedcites [3] Ji, C., Stockbridge, R. B. & Miller, C. Bacterial fluoride resistance, Fluc channels, and the weak acid accumulation effect. J. Gen. Physiol. 144, 257–261 (2014) source
The Introduction states that many bacteria, yeasts, and protozoa carry membrane F− exporters to keep cytoplasmic F− below inhibitory concentrations. The Discussion adds that Fluc channels export F− and protect microorganisms from its toxicity. (LLM, conf=0.95)
- Supportedcites [4] Smith, K. D. et al. Yeast FEX1 is a constitutively expressived fluoride channel in with functional asymmetry of its two homologous domains. J. Biol. Chem. 290, 19874–19887 (2015) source
The paper states that fluoride-exporting proteins protect organisms by removing fluoride from cells (Abstract). It also says that yeast FEX proteins maintain a low intracellular fluoride concentration under external fluoride exposure, whereas yeast lacking them are much more sensitive to fluoride (passage 8). (LLM, conf=0.92)
- Supportedcites [8] Stockbridge, R. B. et al. Fluoride resistance and transport by riboswitch-controlled CLC antiporters. Proc. Natl Acad. Sci. USA 109, 15289–15294 (2012) source
The paper explains that environmental fluoride can accumulate in bacterial cytoplasm and that a fluoride-export pathway would lower its concentration below extracellular levels. In the Results, CLC-F proteins protect E. coli from fluoride toxicity, and the authors demonstrate fluoride transport by the proteins in liposomes. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the dual-topology arrangement includes a centrally coordinated cation, most likely Na+.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we solved crystal structures of two bacterial Fluc homologues in complex with three different monobody inhibitors, with and without F- present, to a maximum resolution of 2.1 Å.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The structures reveal a surprising “double-barrelled” channel architecture in which two F- ion pathways span the membrane”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“a set of four electron densities located in crevices between TM2, TM3b, and TM4 near the channel’s periphery, distant from the vestibules and the central plug”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Prominent among these are a strongly conserved asparagine (N43) in TM2 and two conserved serines (S108, S112) in TM4.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
boosted- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the crevice-facing surface of TM4 is lined with H-donating side chains, as manifested by every fourth residue in the sequences of Bpe (Y104, S108, S112, T116) or Ec2 (S102, H106, S110, T114).”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A conspicuous, universally conserved TM1 arginine residue (R23) protrudes into each vestibule”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The protein is capped on both ends by the S7 monobody (Fig. 1c).”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No aqueous pore connecting the vestibules is visible in this low-resolution structure.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plain- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 26
- The quote only partly states this claim. 1
- It may state two separate claims as one. 35
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This monobody was selected from a library designed to target convex protein surfaces14”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Partly supportedcites [14] Koide, A., Wojcik, J., Gilbreth, R. N., Hoey, R. J. & Koide, S. Teaching an old scaffold new tricks: monobodies constructed using alternative surfaces of the FN3 scaffold. J. Mol. Biol. 415, 393–405 (2012) sourceExperimental — accuracy not yet measured
The Results (Library Design; Crystal structures of monobody-target complexes confirm library designs) describe a side-and-loop library intended to recognize convex surfaces and report that SH13, a monobody from that library, binds a convex Abl SH2 surface. Our copy does not identify S7 as a monobody selected from that library, so it supports the library-design point but not the claim about S7 specifically. (LLM, conf=0.84)
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
In the paper
“however diffraction to 3.6 Å Bragg spacing was obtained with monobody Mb(Bpe-S7)6, hereafter denoted S7.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not checked yetcites [6] Stockbridge, R. B., Koide, A., Miller, C. & Koide, S. Proof of dual-topology architecture of Fluc F− channels with monobody blockers. Nature Commun. 5, 5120 (2014) source
plainSingle case- Asserted: passes — The authors put it forward as true.
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The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additional densities also appear in Ec2 in the general vicinity as the F2 ions in Bpe, but at this lower resolution and without supporting experimental evidence, these densities in Ec2 cannot be unambiguously assigned.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Most of the channel’s aqueous-exposed surface is covered by monobody, consistent with S7 block of Bpe seen in single-channel recordings (Fig. 1c).”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The channel is hourglass-shaped, with wide vestibules symmetrically opening to the two aqueous solutions (Fig. 1b) separated by a solid plug of protein 10-15 Å thick.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The Ec2 and Bpe folds are identical (Cα rmsd 0.6 Å), with inferred Na+ density appearing in equivalent locations.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These mutations preserve the channel's integrity, since F- efflux is blocked 50-80% by 6µM monobody”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“We next examined the functional consequences of mutating each of three conserved Bpe residues coordinating the F- densities: F82, F85, and N43. We did not observe single-channel activity in electrical recordings, but more sensitive “anion-dump” experiments22,23 reveal dramatic changes in F- permeation”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not checked yetcites [22] Walden, M. et al. Uncoupling and turnover in a Cl−/H+ exchange transporter. J. Gen. Physiol. 129, 317–329 (2007) source
Checked before — its earlier verdict is held back until a new check runs.
- Not checked yetcites [23] Brammer, A. E., Stockbridge, R. B. & Miller, C. F. F−/Cl− selectivity in CLCF-type F−/H+ antiporters. J. Gen. Physiol. 144, 129–136 (2014) source
Checked before — its earlier verdict is held back until a new check runs.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Not checked yet
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Two strong difference densities lie at precisely the same locations as the F1 ions in Bpe, coordinated identically”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“All 16 Se plus 4 Hg sites were located using SHELX and this dataset was combined with the initial 3.6 Angstrom Hg derivatized data.”
§ Crystal structures of a double-barrelled fluoride ion channel > Methods > Structure Determination
What the sources say
- Not matchedcites SHELX
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“For F85I and F82I, efflux of F- is 2 and 3 orders of magnitude slower, respectively, than for wild type (~3x105 s-1)15”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not checked yetcites [15] Turman, D. L., Nathanson, J. T., Stockbridge, R. B., Street, T. O. & Miller, C. Two-sided block of a dual-topology F– channel. Proc. Natl Acad. Sci. USA 112, 5697–5701 (2015) source
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“L2, though binding in an orientation different from S7's, also extends a long loop 8-10 Å into the vestibule, occluding much of the channel’s water-exposed surface.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“An 8-residue loop on the monobody plunges deeply into each vestibule, contacting the channel mainly via side chains.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We did not observe higher resolution diffraction in the Native crystals, which typically gave diffraction between 3.6 - 3.8 Angstroms.”
§ Crystal structures of a double-barrelled fluoride ion channel > Methods > Structure Determination
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In stark contrast to the pH-independent activity of wild type Bpe and the F85I mutant (Extended Data Fig. 5), F- efflux in N43D falls with increasing pH and is extinguished at pH 9”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Alignments (Extended Data Fig. 7) show that “pore-2,” where most residues arise from the C-terminal domain, retains the strict sequence conservation typical of the homodimeric bacterial Flucs, while the equivalent residues of “pore-1,” mostly in the N-terminal domain, are far less conserved, notably along the TM4 polar track.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These particular residues are only modestly conserved among Fluc channels, but H-bond donors reliably appear here throughout the family.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“The four Hg sites were located using the single wavelength anomalous dispersion (SAD) method as implemented in SHELX36 with the positions further refined and initial phases calculated using SHARP37 with solvent flattening in SOLOMON38.”
§ Crystal structures of a double-barrelled fluoride ion channel > Methods > Structure Determination
What the sources say
- Not matchedcites SHELX36
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites SHARP37
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites SOLOMON38
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
- Not matched
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Bpe is an antiparallel homodimer in which each subunit consists of four transmembrane helices with an overall fold novel among membrane proteins.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The space group was determined to be P21212 with two Bpe dimers and four S7 monobodies in the asymmetric unit (Extended data Figure 1).”
§ Crystal structures of a double-barrelled fluoride ion channel > Methods > Structure Determination
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“The two pathways are not segregated to each subunit as in CLC channels24; instead each pore comprises side chains from TM2, TM3b, and TM4 of one subunit plus the TM3-break phenylalanine from the opposing subunit.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not checked — no full text of the sourcecites [24] Weinreich, F. & Jentsch, T. J. Pores formed by single subunits in mixed dimers of different CLC chloride channels. J. Biol. Chem. 276, 2347–2353 (2001) source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Phases were calculated using Se-SAD with 8 Se sites, and processed as above.”
§ Crystal structures of a double-barrelled fluoride ion channel > Methods > Structure Determination
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“For the Bpe-L2 crystals, data were similarly processed and scaled in spacegroup P1.”
§ Crystal structures of a double-barrelled fluoride ion channel > Methods > Structure Determination
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“F- turnover by WT exceeds response time of the electrode.”
§ Crystal structures of a double-barrelled fluoride ion channel > Extended Data
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For the Ec2-S9 crystals the data were processed as above with space group P41.”
§ Crystal structures of a double-barrelled fluoride ion channel > Methods > Structure Determination
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The electron density maps clearly showed major differences in the selected, variable regions of the monobody.”
§ Crystal structures of a double-barrelled fluoride ion channel > Methods > Structure Determination
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“No prior phase information was used during the refinement, however refinement was improved following anisotropic truncation of the structure factors.”
§ Crystal structures of a double-barrelled fluoride ion channel > Methods > Model building and refinement
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The experimental electron density maps were of exceptional quality following phase extension to the highest resolution shell of 2.58 Å.”
§ Crystal structures of a double-barrelled fluoride ion channel > Methods > Structure Determination
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“microorganisms export this anion through F--specific ion channels of the Fluc family1–4.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not checked yetcites [1] Baker, J. L. et al. Widespread genetic switches and toxicity resistance proteins for fluoride. Science 335, 233–235 (2012) source
- Not checked yetcites [2] Li, S. et al. Eukaryotic resistance to fluoride toxicity mediated by a widespread family of fluoride export proteins. Proc. Natl Acad. Sci. USA 110, 19018–19023 (2013) source
- Not checked yetcites [3] Ji, C., Stockbridge, R. B. & Miller, C. Bacterial fluoride resistance, Fluc channels, and the weak acid accumulation effect. J. Gen. Physiol. 144, 257–261 (2014) source
- Not checked yetcites [4] Smith, K. D. et al. Yeast FEX1 is a constitutively expressived fluoride channel in with functional asymmetry of its two homologous domains. J. Biol. Chem. 290, 19874–19887 (2015) source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“including extreme selectivity for F- over Cl- and dual-topology dimeric assembly5–6.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not checked yetcites [5] Stockbridge, R. B., Robertson, J. L., Kolmakova-Partensky, L. & Miller, C. A family of fluoride-specific ion channels with dual-topology architecture. eLife 2, e01084. (2013) source
- Not checked yetcites [6] Stockbridge, R. B., Koide, A., Miller, C. & Koide, S. Proof of dual-topology architecture of Fluc F− channels with monobody blockers. Nature Commun. 5, 5120 (2014) source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The fluoride anion, ubiquitous in the aqueous biosphere throughout evolutionary time, is a xenobiotic inhibitor of essential phosphoryl-transfer enzymes7.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not matchedcites [7] Adamek, E., Pawlowska-Goral, K. & Bober, K. In vitro and in vivo effects of fluoride ions on enzyme activity. Ann. Acad. Med. Stetin. 51, 69–85 (2005)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Third, the channel’s extreme F- selectivity may arise from the narrow bore of the permeation pathway, which would exclude Cl- ions while permitting the smaller F- to enter.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Ec2-S9 crystals diffracting to 2.6 Å were grown from detergent in the presence of F-, and to avoid model bias a structure was solved using SAD phasing with selenomethionine-labelled protein”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plainSingle case- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“First, a buried Na+ ion occupying a unique position on the twofold axis invites us to view this cation as an intrinsic structural element stabilizing the dimer interface.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“was established definitively by two-sided block of single channels by “monobodies,” engineered proteins selected as high-affinity binding partners from combinatorial libraries6.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not checked yetcites [6] Stockbridge, R. B., Koide, A., Miller, C. & Koide, S. Proof of dual-topology architecture of Fluc F− channels with monobody blockers. Nature Commun. 5, 5120 (2014) source
boosteddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Bpe constructs carried two functionally neutral mutations to enhance expression, R29K/E94S or, for Hg labeling, R29K/E94C.”
§ Crystal structures of a double-barrelled fluoride ion channel > Methods > Biochemical
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Ec2 constructs bore a single functionally neutral, expression-enhancing mutation, R25K, and, for selenomethionine incorporation, an additional methionine was introduced (A51M) to enhance phasing power.”
§ Crystal structures of a double-barrelled fluoride ion channel > Methods > Biochemical
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because these pathways are extremely narrow, protein dynamics may be necessary to allow F- permeation and of course the monobodies might force a conformation in which the two pores are less ‘open’ than in the fully conducting state.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“We recently established5,6 that Fluc proteins are ion channels with two unusual properties: an exceedingly high specificity (>104) for F- over Cl–, and a dual-topology dimeric architecture”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not checked yetcites [5] Stockbridge, R. B., Robertson, J. L., Kolmakova-Partensky, L. & Miller, C. A family of fluoride-specific ion channels with dual-topology architecture. eLife 2, e01084. (2013) source
- Not checked yetcites [6] Stockbridge, R. B., Koide, A., Miller, C. & Koide, S. Proof of dual-topology architecture of Fluc F− channels with monobody blockers. Nature Commun. 5, 5120 (2014) source
boosted- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Dual-topology dimeric construction is known in small multidrug transporters9–11 but has not been previously observed in ion channels.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not checked yetcites [9] Ubarretxena-Belandia, I., Baldwin, J. M., Schuldiner, S. & Tate, C. G. Three-dimensional structure of the bacterial multidrug transporter EmrE shows it is an asymmetric homodimer. EMBO J. 22, 6175–6181 (2003) source
Checked before — its earlier verdict is held back until a new check runs.
- Not checked — no full text of the sourcecites [10] Schuldiner, S. EmrE, a model for studying evolution and mechanism of ion-coupled transporters. Biochim. Biophys. Acta 1794, 748–762 (2009) source
- Not checked yetcites [11] Morrison, E. A. et al. Antiparallel EmrE exports drugs by exchanging between asymmetric structures. Nature 481, 45–50 (2011) source
Checked before — its earlier verdict is held back until a new check runs.
boosted- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Not checked yet
In the paper
“Recent experiments buttress this idea by showing that mutations of several C-terminal domain residues in pore-2 produce F- hypersensitivity in yeast, whereas mutations of N-terminal domain, pore-1 counterparts are relatively harmless4.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not checked yetcites [4] Smith, K. D. et al. Yeast FEX1 is a constitutively expressived fluoride channel in with functional asymmetry of its two homologous domains. J. Biol. Chem. 290, 19874–19887 (2015) source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Though unexpected, this idea does not clash with any electrophysiological experiments, and double-pore assembly was explicitly cited previously as a possible though unlikely architecture consistent with the channel’s functional behaviour5.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not checked yetcites [5] Stockbridge, R. B., Robertson, J. L., Kolmakova-Partensky, L. & Miller, C. A family of fluoride-specific ion channels with dual-topology architecture. eLife 2, e01084. (2013) source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A structure was solved, with phases initially determined by single-wavelength anomalous diffraction (SAD) of Bpe labelled with Hg at a unique cysteine residue, and improved with Hg-labelled selenomethionine-substituted samples”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“This type of coordination is reminiscent of the phenylalanine rings of a proposed Cl--binding site in the bestrophin channel21.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not checked yetcites [21] Kane Dickson, V., Pedi, L. & Long, S. B. Structure and insights into the function of a Ca2+-activated Cl− channel. Nature 516, 213–218 (2014) source
Checked before — its earlier verdict is held back until a new check runs.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“This homologue of only 33% identity shows similar electrophysiological behavior to Bpe and is blocked by S9 at nanomolar concentrations6.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not checked yetcites [6] Stockbridge, R. B., Koide, A., Miller, C. & Koide, S. Proof of dual-topology architecture of Fluc F− channels with monobody blockers. Nature Commun. 5, 5120 (2014) source
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The two F- ions of each pair lie in a vertical line tilted slightly off normal to the membrane plane, and so might mark a narrow permeation pathway.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“With a deficit of H-bond acceptors, the coordination shells observed here would be chemically inimical to ordered waters, which cannot be distinguished from F- based on x-ray scattering alone.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Two-pore assembly neatly accounts for evolutionary drift in eukaryotic Fluc channels, all of which consist of an inverted repeat of two homologous Fluc domains fused into a single polypeptide4,5.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not checked yetcites [4] Smith, K. D. et al. Yeast FEX1 is a constitutively expressived fluoride channel in with functional asymmetry of its two homologous domains. J. Biol. Chem. 290, 19874–19887 (2015) source
- Not checked yetcites [5] Stockbridge, R. B., Robertson, J. L., Kolmakova-Partensky, L. & Miller, C. A family of fluoride-specific ion channels with dual-topology architecture. eLife 2, e01084. (2013) source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Edge-on aromatic liganding of anions is rare but not unprecedented in proteins19, and F- coordination by aromatic edges appears in many small-molecule structures20.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not checked — no full text of the sourcecites [19] Philip, V. et al. A survey of aspartate-phenylalanine and glutamate-phenylalanine interactions in the protein data bank: searching for anion-π pairs. Biochemistry 50, 2939–2950 (2011) source
- Not checked — no full text of the sourcecites [20] Allen, F. H. The Cambridge Structural Database: a quarter of a million crystal structures and rising. Acta Crystallogr. B 58, 380–388 (2002) source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Although coordination by only four oxygen ligands is uncommon for Na+, it is nevertheless seen in ~15% of Na+-binding sites in the protein database18.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
What the sources say
- Not checked — no full text of the sourcecites [18] Lev, B. R. B. & Noskov, S. Y. in Encyclopedia of Metalloproteins (eds Kretsinger, R. H. et al.) 2112–2118 (Springer, 2013) source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The pore, though narrow, is lined with H-bonding residues and so could provide a polar conduit for the ion’s journey across the membrane span.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This inference makes it difficult to resist the conclusion that Flucs are double-barrelled F- channels, with the observed F- ions marking the ion-selective pathways.”
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To avoid biasing the model, NCS was not employed except at the final round of refinement to improve model geometry.”
§ Crystal structures of a double-barrelled fluoride ion channel > Methods > Model building and refinement
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No prior phase information was used during the refinement, however refinement was improved following anisotropic truncation of the structure factors.”
§ Crystal structures of a double-barrelled fluoride ion channel > Methods > Model building and refinement
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Each value represents mean ± s.e. of 3 determinations calculated from initial efflux rate.”
§ Crystal structures of a double-barrelled fluoride ion channel > Extended Data
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Channels were recorded in the presence of 300 mM N-methyl-glucamine-fluoride, from which all small cations were rigorously excluded.”
§ Crystal structures of a double-barrelled fluoride ion channel > Extended Data
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
In the paper
“Model validation was carried out using the Molprobity server44.”
§ Crystal structures of a double-barrelled fluoride ion channel > Methods > Model building and refinement
What the sources say
- Not matchedcites [44]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In the heterodimeric Fluc and FEX proteins, essential pore-lining residues are conserved in only one of the two domains(3, 66, 73), providing a case study in how redundant features degrade upon gene duplication, fusion, and genetic drift.”
From Membrane exporters of fluoride ion (2021) · cites this paper as [73]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Of these various topologies, the dual topology homodimers, from Bordetella pertussis (Fluc-Bpe) and an E. coli virulence plasmid (Fluc-Ec2), are the only ones that have been structurally characterized(63, 73, 74).”
From Membrane exporters of fluoride ion (2021) · cites this paper as [73]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Of dozens of mutations, none have allowed detectable throughput of any other anion, and increasing the bore of the channel by paring back sidechains has not yet been shown to decrease selectivity(73, 75, 76, 85).”
From Membrane exporters of fluoride ion (2021) · cites this paper as [73]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Alteration of N43 typically eliminates fluoride transport entirely (73, 85); the polar track residues, like the sidechains that coordinate F0, are somewhat more tolerant of alanine substitution(85).”
From Membrane exporters of fluoride ion (2021) · cites this paper as [73]
Experimental — accuracy not yet measuredIn the citing paper
“FEX proteins are related structurally to the Flucs but possess a more complex two-domain fold83,87.”
From The link between ancient microbial fluoride resistance mechanisms and bioengineering organofluorine degradation or synthesis (2024) · cites this paper as [83]
In the citing paper
“The Flucs assemble as unusual antiparallel dimers, where one protomer is inserted into the membrane facing out, and the other is inserted into the membrane facing in81,83.”
From The link between ancient microbial fluoride resistance mechanisms and bioengineering organofluorine degradation or synthesis (2024) · cites this paper as [83]
In the citing paper
“This glutamate is extremely well-conserved among fluoride channels and follows the same pattern of conservation/degradation in the different domains of the eukaryotic channels as other pore-lining residues(73).”
From Membrane exporters of fluoride ion (2021) · cites this paper as [73]
In the citing paper
“Mutation of either F82 or F85 to a non-polarizable hydrophobic residue like isoleucine greatly reduces or abolishes F− transport, depending on the homologue(73, 76).”
From Membrane exporters of fluoride ion (2021) · cites this paper as [73]
In the citing paper
“Of dozens of mutations, none have allowed detectable throughput of any other anion, and increasing the bore of the channel by paring back sidechains has not yet been shown to decrease selectivity(73, 75, 76, 85).”
From Membrane exporters of fluoride ion (2021) · cites this paper as [73]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Crystal structures of a double-barrelled fluoride ion channel > Abstract
“In stark contrast to the pH-independent activity of wild type Bpe and the F85I mutant (Extended Data Fig. 5), F- efflux in N43D falls with increasing pH and is extinguished at pH 9 (Fig. 3d)”
§ Crystal structures of a double-barrelled fluoride ion channel > Extended Data
“Figure: Extended Data Figure 6 Liposome flux assays of Bpe variants. Upper three panels: F- transport from liposomes by Bpe mutants F82I, F85I, and N43D, in the presence and absence of 6 uM blocking monobody. F- efflux from proteoliposomes (0.2 µg protein/mg lipid for Phe mutants; 1 µg protein/mg lipid for N43D) was monitored with a F- electrode and normalized against total trapped F-. Lower panel: F- dump by F85I measured at pH 7 and pH 9.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Crystal structures of a double-barrelled fluoride ion channel > Extended Data
“| Resolution (Å) | 48 – 3.6 (3.7 – 3.6) | 48 – 3.6 (3.7 –3.6) | 57 – 4.8 (4.7 – 4.8) | 41 – 2.5 (2.5 – 2.1) | 38 – 3.0 (3.1 – 3.0) | 25-2.6 (2.7 – 2.6) |”
§ Crystal structures of a double-barrelled fluoride ion channel > Extended Data
“| Resolution (Å) | 114.7 – 3.6 | | | 40.9 – 2.1 | 38.1 – 3.0 | 24.2 – 2.6 |”
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Metadata
- Authors
- Stockbridge, R. B., Kolmakova-Partensky, L., Shane, T., Koide, A., Koide, S., Miller, C., & Newstead, S.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Chicago (US)
- University of Oxford (GB)
- Corresponding author
- Newstead, Simon
- Venue
- Nature
- Published
- 2015-09
- Volume
- 525
- Issue
- 7570
- Pages
- 548-551
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4876929
- OpenAlex
- W1893822674
- Cited by
- 119
- References
- 42
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 14 · 2023: 6 · 2022: 11 · 2021: 14 · 2020: 14 · 2019: 6 · 2018: 15 · 2017: 15 · 2016: 9 · 2015: 3
- FWCI
- 4.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Wellcome Trust (102890/Z/13/Z, 102890)
- National Institute of General Medical Sciences (K99GM111767, R01GM107023, U54GM087519)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- anion selectivity, anion coordination, fluoride toxicity, sodium cation coordination, crystal structure
- MeSH terms
- Anions, Bacterial Proteins, Cell Membrane, Fluorides, Ion Channels, Models, Biological, Models, Molecular, Phenylalanine, Protein Conformation, Crystallography, X-Ray
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