Localization of the Ribosomal Protection Protein Tet(O) on the Ribosome and the Mechanism of Tetracycline Resistance
Open accessAbstract
Tet(O) belongs to a class of ribosomal protection proteins that mediate tetracycline resistance. It is a G protein that shows significant sequence similarity to elongation factor EF-G. Here we present a cryo-electron microscopic reconstruction, at 16 A resolution, of its complex with the E. coli 70S ribosome. Tet(O) was bound in the presence of a noncleavable GTP analog to programmed ribosomal complexes carrying fMet-tRNA in the P site. Tet(O) is directly visible as a mass close to the A-site region, similar in shape and binding position to EF-G. However, there are important differences. One of them is the different location of the tip of domain IV, which in the Tet(O) case, does not overlap with the ribosomal A site but is directly adjacent to the primary tetracycline binding site. Our findings give insights into the mechanism of tetracycline resistance.
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The existing 16-Å reconstruction of Tet(O)-70S is unsuitable for building an atomic model.
“The existing 16-Å reconstruction of Tet(O)-70S 9 is unsuitable for this purpose.”
From Mechanism of tetracycline resistance by ribosomal protection protein Tet(O) (2013) · cites this paper as [9]
The density for Tet(O) in the improved map is at a position that agrees with the earlier study, but its boundary and shape are better defined in the context of the 70S ribosome.
“The density for Tet(O) in this improved map is at a position which agrees with that described in the earlier study 9, but boundary and shape are better defined in the context with the 70S ribosome (Fig. 1).”
From Mechanism of tetracycline resistance by ribosomal protection protein Tet(O) (2013) · cites this paper as [9]
Tet(O) shares five structural domains with EF-G; the first two contain the GTP-binding site and are close to the GTP-associated center of the 50S subunit, while the other three are distinct for Tet(O) and associated with its specific functions.
“Sequence homology shows that Tet(O) shares the five structural domains with EF-G, the first two containing the GTP-binding site and being close to the GTP-associated center of the 50S ribosomal subunit, while the other three domains are distinct for Tet(O) and associated with its specific functions 9,10.”
From Mechanism of tetracycline resistance by ribosomal protection protein Tet(O) (2013) · cites this paper as [9]
A previous 16 Å cryo-EM study showed that Tet(O) has a similar shape to EF-G and binds to the same general site within the intersubunit cavity of the ribosome.
“A previous Tet(O) cryo-EM study 9, with a density map at a resolution of 16 Å, allowed the visualization of Tet(O) bound to the Escherichia coli ribosome, revealing that Tet(O) indeed has a similar shape as EF-G and binds to the same general site within the intersubunit cavity of the ribosome.”
From Mechanism of tetracycline resistance by ribosomal protection protein Tet(O) (2013) · cites this paper as [9]
The presence of the 465-loop of Tet(O) at the base of the 30S subunit's beak prevents the head of the 30S subunit from rotating, a motion required in the normal course of mRNA-tRNA translocation.
“The presence of the 465-loop of Tet(O) at the base of the 30S subunit’s beak prevents the head of the 30S subunit from rotating, a motion required in the normal course of mRNA-tRNA translocation 9.”
From Mechanism of tetracycline resistance by ribosomal protection protein Tet(O) (2013) · cites this paper as [9]
The proposed conformational change resulting in tetracycline release probably involves h34.
“The proposed conformational change resulting in tetracycline release probably involves h34 as (i) h34 forms an integral part of the primary tetracycline binding site (4, 37), (ii) cryo-EM reconstructions show that domain IV of Tet(O) contacts the base of h34 (45), and (iii) Tet(O) protects C1214 at the base of h34 from chemical modification by DMS (12).”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [45]
When Tet(O) binds the ribosome, it does not directly overlap the primary tetracycline binding site.
“cryo-EM studies demonstrated that when Tet(O) binds the ribosome, it does not directly overlap the primary tetracycline binding site”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [45]
Protection of C1214 from DMS modification indicates that this base is directly shielded by Tet(O), supported by cryo-EM.
“The protection of C1214 from DMS modification would indicate that this base is directly shielded by Tet(O), and this conclusion is supported by the fact that the Tet(O) binding site observed by cryo-EM approaches C1214 (Fig. 4B).”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [45]
Upon binding, Tet(O) contacts the base of h34, causing a disturbance in this helix that is propagated to the primary tetracycline-binding site, releasing the drug.
“Spahn et al. (45) hypothesize that, upon binding, Tet(O) contacts the base of h34, which in turn causes a disturbance in this helix, which is propagated to the primary tetracycline-binding site, releasing the drug.”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [45]
A direct interaction between Tet(O) and tetracycline bound to the primary site cannot be absolutely discounted, although chemical probing and cryo-EM suggest it is not the case.
“It should be noted, however, that a direct interaction between Tet(O) and tetracycline bound to the primary site cannot be absolutely discounted, although both chemical probing and cryo-EM suggest this is not the case (12, 45).”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [45]
EF-G and Tet(O) ribosomal contacts differ primarily in the vicinity of domain IV, where EF-G contacts H69 of 23S rRNA and Tet(O) interacts with h18/34 of 16S rRNA.
“Furthermore, a comparison of the EF-G and Tet(O) ribosomal contacts indicates that they differ primarily in the vicinity of domain IV (Table 1), where EF-G contacts H69 of the 23S rRNA (21, 45) and Tet(O) interacts with h18/34 of the 16S rRNA (45).”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [45]
The majority of interactions between Tet(O) and the ribosome are between Tet(O) and rRNA, with the only exception being a single interaction between domain III of Tet(O) and ribosomal protein S12.
“In the cryo-EM study, Spahn et al. localize the sites of interaction between Tet(O) and the ribosome (Table 1), demonstrating that that the majority of the interactions are between Tet(O) and the rRNA (45). The only exception is a single interaction between domain III of Tet(O) and the ribosomal protein S12 (45).”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [45]
These changes could be mediated by S12, which is in close proximity to the top of h44 and also appears to interact with Tet(O).
“These changes could be mediated by S12, which is in close proximity to the top of h44 (43, 58) and also appears to interact with Tet(O) (45).”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [45]
Tet(O) triggers the release of tetracycline through an allosteric mechanism.
“Spahn et al. (45) proposed that Tet(O) triggers the release of tetracycline through an allosteric mechanism.”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [45]
Differences in domain IV may serve to distinguish Tet(O) and EF-G with respect to their activities; domain IV of EF-G more intimately overlaps with the A site-bound tRNA, consistent with its role in translocation, whereas interaction of domain IV of Tet(O) and h34 of the 30S subunit is consistent with its role in tetracycline release because h34 is a component of the primary tetracycline binding.
“In this case, these differences in domain IV may serve to distinguish Tet(O) and EF-G with respect to their activities; namely, domain IV of EF-G more intimately overlaps with the A site-bound tRNA, an idea that is consistent with the role of domain IV of EF-G in translocation. In contrast, the interaction of domain IV of Tet(O) and h34 of the 30S subunit is consistent with its role in tetracycl”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [45]
Tet(O) and EF-G bind to a common site located at the interface of the ribosomal subunit on the A site side, at the base of the L7/L12 stalk.
“Also evident in the reconstruction is that Tet(O) and EF-G are binding to a common site located at the interface of the ribosomal subunit on the A site side, at the base of the L7/L12 stalk (Fig. 3), in agreement with Dantley et al. (15).”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [45]
Enhancement of A1408 by DMS modification indicates that Tet(O) is inducing long-range rearrangements in the ribosome.
“Furthermore, an enhancement of chemical modification is clearly indicative of a conformational change; therefore, this result can be taken to indicate that Tet(O) is inducing long-range rearrangements in the ribosome.”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [45]
The combination of biochemical and structural data has provided a plausible mechanism that explains the mode of RPP action in molecular detail: the RPPs interact with the base of h34, resulting in an allosteric disruption of primary tetracycline binding and consequently releasing the drug.
“Furthermore, the combination of these data has provided a plausible mechanism that explains the mode of RPP action in molecular detail, namely that the RPPs interact with the base of h34, resulting in an allosteric disruption of primary tetracycline binding and consequently releasing the drug (45).”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [45]
When biochemical and structural data describing the RPP's ribosomal binding site are combined, the interaction of the RPP with the ribosome can be modeled with high precision.
“When the biochemical (11, 12, 15) and structural (45) data describing the RPP's ribosomal binding site are combined, the interaction of the RPP with the ribosome can be modeled with high precision (Table 1).”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [45]
The overall orientation of TetM on the ribosome is similar to that observed previously for TetO.
“The overall orientation of TetM on the ribosome is similar to that observed previously for TetO (14), although no direct comparison can be made because the TetO map was not deposited in a public database.”
From Structural basis for TetM-mediated tetracycline resistance (2012) · cites this paper as [14]
TetO was suggested to chase tetracycline from the ribosome indirectly via inducing local disturbances within h34.
“As TetO is not observed to directly interact with C1054 or A1408 (14), TetO was suggested to chase tetracycline from the ribosome indirectly via inducing local disturbances within h34 (9,14,15).”
From Structural basis for TetM-mediated tetracycline resistance (2012) · cites this paper as [14]
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- Authors
- Spahn, C. M. T., Blaha, G., Agrawal, R. K., Penczek, P., Grassucci, R. A., Trieber, C. A., Connell, S. R., Taylor, D. E., Nierhaus, K. H., & Frank, J.
- Affiliations
- Wadsworth Center (US)
- Max Planck Institute for Molecular Genetics (DE)
- State University of New York (US)
- University of Alberta (CA)
- Corresponding author
- Frank, Joachim
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2001-05
- Volume
- 7
- Issue
- 5
- Pages
- 1037-1045
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W1999497853
- Cited by
- 81
- References
- 45
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 3 · 2022: 1 · 2020: 2 · 2019: 2 · 2018: 4 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 9 · 2013: 3 · 2012: 6
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01-GM-55440, R01GM055440, R37GM029169, R37 GM-29169)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- tetO, ribosomal protection proteins, tetracycline resistance, ribosome, G proteins, Escherichia coli, 70S ribosome, A-site, P site, fMet-tRNA, cryo-electron microscopy, domain IV
- MeSH terms
- Bacterial Proteins, Binding Sites, Carrier Proteins, Escherichia coli, Models, Molecular, Molecular Conformation, Ribosomes, Tetracycline Resistance, Protein Biosynthesis, RNA-Binding Proteins, Protein Structure, Tertiary, Cryoelectron Microscopy
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