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Cited by 70Protein Kinase Regulation and GTPase SignalingEnzyme Structure and FunctionProtein Structure and Dynamics

IP6K Structure and the Molecular Determinants of Catalytic Specificity in an Inositol Phosphate Kinase Family

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Wang, Huanchen, DeRose, Eugene F., London, Robert E., Shears, Stephen B.·2014·Nature Communications
DOI 10.1038/ncomms5178PMC PMC4141478
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Abstract

Inositol trisphosphate kinases (IP3Ks) and inositol hexakisphosphate kinases (IP6Ks) each regulate specialized signalling activities by phosphorylating either InsP3 or InsP6 respectively. The molecular basis for these different kinase activities can be illuminated by a structural description of IP6K. Here we describe the crystal structure of an Entamoeba histolytica hybrid IP6K/IP3K, an enzymatic parallel to a 'living fossil'. Through molecular modelling and mutagenesis, we extrapolated our findings to human IP6K2, which retains vestigial IP3K activity. Two structural elements, an α-helical pair and a rare, two-turn 310 helix, together forge a substrate-binding pocket with an open clamshell geometry. InsP6 forms substantial contacts with both structural elements. Relative to InsP6, enzyme-bound InsP3 rotates 55° closer to the α-helices, which provide most of the protein's interactions with InsP3. These data reveal the molecular determinants of IP6K activity, and suggest an unusual evolutionary trajectory for a primordial kinase that could have favored efficient bifunctionality, before propagation of separate IP3Ks and IP6Ks.

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  • Crystal structures of a different IP6K captured with IP3 and IP5 suggest an alternative less energetically costly 180° rotation about an axis at the center of the inositol ring.

    “However, crystal structures of a different IP6K captured with IP3 and IP5 in its active site [51] suggest an alternative and less energetically costly alternative—a 180° rotation about an axis that is at the center of the inositol ring, such that each inositol carbon position is moved to a new position three numbers down, i.e., 1 to 4, 2 to 5, and so on, in order to position the 6 position in line”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [51]

    The Results section, “The Molecular determinants of Inositol Phosphate binding” (page unavailable), reports EhIP6KA crystal structures with InsP3 and InsP5 and models a 180° reorientation of bound InsP3. It describes a flip across the ring’s 1/4 axis, however, not the claimed rotation that moves carbon 1 to position 4, and it does not assess whether that rotation is less energetically costly. (LLM, conf=0.86)

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Cited by

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Authors
Wang, H., DeRose, E. F., London, R. E., & Shears, S. B.
Affiliations
National Institutes of Health (US)
Corresponding author
Shears, Stephen B.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2014-06-24
Volume
5
Issue
1
Pages
4178-4178
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms5178
PMC
PMC4141478
OpenAlex
W2072044184
Cited by
70
References
2
Citations by year
2026: 3 · 2025: 9 · 2024: 7 · 2023: 10 · 2022: 4 · 2021: 6 · 2020: 1 · 2019: 5 · 2018: 5 · 2017: 8 · 2016: 5 · 2015: 5 · 2014: 2
FWCI
2.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of Environmental Health Sciences (ZIAES080046)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
inositol hexakisphosphate kinase, Entamoeba histolytica, crystal structure, substrate binding pocket, 310-helix, substrate orientation, catalytic specificity, kinase evolution
MeSH terms
Adenosine Triphosphate, Binding Sites, Catalysis, Entamoeba histolytica, Multigene Family, Humans, Inositol Phosphates, Sensitivity and Specificity, Protozoan Proteins, Phosphotransferases (Phosphate Group Acceptor), Crystallography, X-Ray, Evolution, Molecular

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