Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome
Abstract
Sarecycline is a new narrow-spectrum tetracycline-class antibiotic approved for the treatment of acne vulgaris. Tetracyclines share a common four-ring naphthacene core and inhibit protein synthesis by interacting with the 70S bacterial ribosome. Sarecycline is distinguished chemically from other tetracyclines because it has a 7-[[methoxy(methyl)amino]methyl] group attached at the C7 position of ring D. To investigate the functional role of this C7 moiety, we determined the X-ray crystal structure of sarecycline bound to the Thermus thermophilus 70S ribosome. Our 2.8-Å resolution structure revealed that sarecycline binds at the canonical tetracycline binding site located in the decoding center of the small ribosomal subunit. Importantly, unlike other tetracyclines, the unique C7 extension of sarecycline extends into the messenger RNA (mRNA) channel to form a direct interaction with the A-site codon to possibly interfere with mRNA movement through the channel and/or disrupt A-site codon–anticodon interaction. Based on our biochemical studies, sarecycline appears to be a more potent initiation inhibitor compared to other tetracyclines, possibly due to drug interactions with the mRNA, thereby blocking accommodation of the first aminoacyl transfer RNA (tRNA) into the A site. Overall, our structural and biochemical findings rationalize the role of the unique C7 moiety of sarecycline in antibiotic action.
- Authors:
-
[2];
[3];
[2]
- Univ. of Illinois, Chicago, IL (United States)
- Yale Univ., New Haven, CT (United States)
- Univ. of Illinois, Chicago, IL (United States). Center for Biomolecular Sciences
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Institutes of Health (NIH), National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID); Almirall, S.A.
- OSTI Identifier:
- 1657561
- Grant/Contract Number:
- AC02-06CH11357; K08-AR070290; R01-GM132302; R21-AI137584; P41-GM103403; S10-RR029205; S10-OD021527
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 117; Journal Issue: 34; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; sarecycline; tetracycline; antibiotic; 70S ribosome; X-ray structure
Citation Formats
Batool, Zahra, Lomakin, Ivan B., Polikanov, Yury S., and Bunick, Christopher G. Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome. United States: N. p., 2020.
Web. doi:10.1073/pnas.2008671117.
Batool, Zahra, Lomakin, Ivan B., Polikanov, Yury S., & Bunick, Christopher G. Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome. United States. https://doi.org/10.1073/pnas.2008671117
Batool, Zahra, Lomakin, Ivan B., Polikanov, Yury S., and Bunick, Christopher G. Wed .
"Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome". United States. https://doi.org/10.1073/pnas.2008671117. https://www.osti.gov/servlets/purl/1657561.
@article{osti_1657561,
title = {Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome},
author = {Batool, Zahra and Lomakin, Ivan B. and Polikanov, Yury S. and Bunick, Christopher G.},
abstractNote = {Sarecycline is a new narrow-spectrum tetracycline-class antibiotic approved for the treatment of acne vulgaris. Tetracyclines share a common four-ring naphthacene core and inhibit protein synthesis by interacting with the 70S bacterial ribosome. Sarecycline is distinguished chemically from other tetracyclines because it has a 7-[[methoxy(methyl)amino]methyl] group attached at the C7 position of ring D. To investigate the functional role of this C7 moiety, we determined the X-ray crystal structure of sarecycline bound to the Thermus thermophilus 70S ribosome. Our 2.8-Å resolution structure revealed that sarecycline binds at the canonical tetracycline binding site located in the decoding center of the small ribosomal subunit. Importantly, unlike other tetracyclines, the unique C7 extension of sarecycline extends into the messenger RNA (mRNA) channel to form a direct interaction with the A-site codon to possibly interfere with mRNA movement through the channel and/or disrupt A-site codon–anticodon interaction. Based on our biochemical studies, sarecycline appears to be a more potent initiation inhibitor compared to other tetracyclines, possibly due to drug interactions with the mRNA, thereby blocking accommodation of the first aminoacyl transfer RNA (tRNA) into the A site. Overall, our structural and biochemical findings rationalize the role of the unique C7 moiety of sarecycline in antibiotic action.},
doi = {10.1073/pnas.2008671117},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 34,
volume = 117,
place = {United States},
year = {Wed Aug 12 00:00:00 EDT 2020},
month = {Wed Aug 12 00:00:00 EDT 2020}
}
Free Publicly Available Full Text
Publisher's Version of Record
Other availability
Search WorldCat to find libraries that may hold this journal
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.
Works referenced in this record:
Retapamulin-Assisted Ribosome Profiling Reveals the Alternative Bacterial Proteome
journal, May 2019
- Meydan, Sezen; Marks, James; Klepacki, Dorota
- Molecular Cell, Vol. 74, Issue 3
High-resolution crystal structures of ribosome-bound chloramphenicol and erythromycin provide the ultimate basis for their competition
journal, February 2019
- Svetlov, Maxim S.; Plessa, Elena; Chen, Chih-Wei
- RNA, Vol. 25, Issue 5
PRODRG : a tool for high-throughput crystallography of protein–ligand complexes
journal, July 2004
- Schüttelkopf, Alexander W.; van Aalten, Daan M. F.
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 8
Comprehensive identification of translation start sites by tetracycline-inhibited ribosome profiling
journal, March 2016
- Nakahigashi, Kenji; Takai, Yuki; Kimura, Michiko
- DNA Research, Vol. 23, Issue 3
Negamycin Interferes with Decoding and Translocation by Simultaneous Interaction with rRNA and tRNA
journal, November 2014
- Polikanov, Yury S.; Szal, Teresa; Jiang, Fuyan
- Molecular Cell, Vol. 56, Issue 4
Probing Translation with Small-Molecule Inhibitors
journal, June 2010
- Blanchard, Scott C.; Cooperman, Barry S.; Wilson, Daniel N.
- Chemistry & Biology, Vol. 17, Issue 6, p. 633-645
Tetracycline antibiotics and resistance mechanisms
journal, May 2014
- Nguyen, Fabian; Starosta, Agata L.; Arenz, Stefan
- Biological Chemistry, Vol. 395, Issue 5
Structural basis for TetM-mediated tetracycline resistance
journal, October 2012
- Donhofer, A.; Franckenberg, S.; Wickles, S.
- Proceedings of the National Academy of Sciences, Vol. 109, Issue 42
Tetracyclines: a pleitropic family of compounds with promising therapeutic properties. Review of the literature
journal, September 2010
- Griffin, Michael O.; Fricovsky, Eduardo; Ceballos, Guillermo
- American Journal of Physiology-Cell Physiology, Vol. 299, Issue 3
Cryo-EM structure of the tetracycline resistance protein TetM in complex with a translating ribosome at 3.9-Å resolution
journal, April 2015
- Arenz, Stefan; Nguyen, Fabian; Beckmann, Roland
- Proceedings of the National Academy of Sciences, Vol. 112, Issue 17
Odilorhabdins, Antibacterial Agents that Cause Miscoding by Binding at a New Ribosomal Site
journal, April 2018
- Pantel, Lucile; Florin, Tanja; Dobosz-Bartoszek, Malgorzata
- Molecular Cell, Vol. 70, Issue 1
Kinetic aspects of tetracycline action on the acceptor (A) site of Escherichia coli ribosomes
journal, July 1982
- Semenkov, Yu. P.; Makarov, E. M.; Makhno, V. I.
- FEBS Letters, Vol. 144, Issue 1
Coot model-building tools for molecular graphics
journal, November 2004
- Emsley, Paul; Cowtan, Kevin
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
Competition between tetracycline and tRNA at both P and A sites of the ribosome of Escherichia coli
journal, March 1987
- Epe, Bernd; Woolley, Paul; Hornig, Horst
- FEBS Letters, Vol. 213, Issue 2
tRNA selection and kinetic proofreading in translation
journal, September 2004
- Blanchard, Scott C.; Gonzalez, Ruben L.; Kim, Harold D.
- Nature Structural & Molecular Biology, Vol. 11, Issue 10
Microbiological Profile of Sarecycline, a Novel Targeted Spectrum Tetracycline for the Treatment of Acne Vulgaris
journal, November 2018
- Zhanel, George; Critchley, Ian; Lin, Lynn-Yao
- Antimicrobial Agents and Chemotherapy, Vol. 63, Issue 1
The Structural Basis for the Action of the Antibiotics Tetracycline, Pactamycin, and Hygromycin B on the 30S Ribosomal Subunit
journal, December 2000
- Brodersen, Ditlev E.; Clemons, William M.; Carter, Andrew P.
- Cell, Vol. 103, Issue 7
PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance
journal, June 2001
- Chopra, Ian; Roberts, Marilyn
- Microbiology and Molecular Biology Reviews, Vol. 65, Issue 2
Inhibition of lipase production in Propionibacterium acnes by sub-minimal-inhibitory concentrations of tetracycline and erythromycin
journal, April 1981
- Webster, G. F.; McGINLEY, K. J.; Leyden, J. J.
- British Journal of Dermatology, Vol. 104, Issue 4
Ribosomal Protection Proteins and Their Mechanism of
Tetracycline
Resistance
journal, December 2003
- Connell, Sean R.; Tracz, Dobryan M.; Nierhaus, Knud H.
- Antimicrobial Agents and Chemotherapy, Vol. 47, Issue 12
Ribosome-Targeting Antibiotics: Modes of Action, Mechanisms of Resistance, and Implications for Drug Design
journal, June 2018
- Lin, Jinzhong; Zhou, Dejian; Steitz, Thomas A.
- Annual Review of Biochemistry, Vol. 87, Issue 1
Molecular Mechanism of Drug-Dependent Ribosome Stalling
journal, April 2008
- Vazquez-Laslop, Nora; Thum, Celine; Mankin, Alexander S.
- Molecular Cell, Vol. 30, Issue 2
Ribosome-targeting antibiotics and mechanisms of bacterial resistance
journal, December 2013
- Wilson, Daniel N.
- Nature Reviews Microbiology, Vol. 12, Issue 1
Tools for Characterizing Bacterial Protein Synthesis Inhibitors
journal, September 2013
- Orelle, Cédric; Carlson, Skylar; Kaushal, Bindiya
- Antimicrobial Agents and Chemotherapy, Vol. 57, Issue 12
Structural basis for potent inhibitory activity of the antibiotic tigecycline during protein synthesis
journal, February 2013
- Jenner, L.; Starosta, A. L.; Terry, D. S.
- Proceedings of the National Academy of Sciences, Vol. 110, Issue 10
Structural insights into the role of rRNA modifications in protein synthesis and ribosome assembly
journal, March 2015
- Polikanov, Yury S.; Melnikov, Sergey V.; Söll, Dieter
- Nature Structural & Molecular Biology, Vol. 22, Issue 4
Antibacterial Therapy for Acne: A Guide to Selection and Use of Systemic Agents
journal, January 2003
- Tan, Hiok-Hee
- American Journal of Clinical Dermatology, Vol. 4, Issue 5
Context-specific inhibition of translation by ribosomal antibiotics targeting the peptidyl transferase center
journal, October 2016
- Marks, James; Kannan, Krishna; Roncase, Emily J.
- Proceedings of the National Academy of Sciences, Vol. 113, Issue 43
Crystal structures of complexes of the small ribosomal subunit with tetracycline, edeine and IF3
journal, April 2001
- Pioletti, M.
- The EMBO Journal, Vol. 20, Issue 8
XDS
journal, January 2010
- Kabsch, Wolfgang
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
The Inhibition Pattern of Antibiotics on the Extent and Accuracy of tRNA Binding to the Ribosome, and Their Effect on the Subsequent Steps in Chain Elongation
journal, January 1983
- Wurmbach, Peter; Nierhaus, Knud H.
- European Journal of Biochemistry, Vol. 130, Issue 1
Context-Specific Action of Ribosomal Antibiotics
journal, September 2018
- Vázquez-Laslop, Nora; Mankin, Alexander S.
- Annual Review of Microbiology, Vol. 72, Issue 1
Phaser crystallographic software
journal, July 2007
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Journal of Applied Crystallography, Vol. 40, Issue 4
Insights into the improved macrolide inhibitory activity from the high-resolution cryo-EM structure of dirithromycin bound to the E. coli 70S ribosome
journal, March 2020
- Pichkur, Evgeny B.; Paleskava, Alena; Tereshchenkov, Andrey G.
- RNA, Vol. 26, Issue 6
Mechanism of tetracycline resistance by ribosomal protection protein Tet(O)
journal, February 2013
- Li, Wen; Atkinson, Gemma C.; Thakor, Nehal S.
- Nature Communications, Vol. 4, Issue 1
Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides
journal, April 2019
- Khabibullina, Nelli F.; Tereshchenkov, Andrey G.; Komarova, Ekaterina S.
- Antimicrobial Agents and Chemotherapy, Vol. 63, Issue 6