Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome

Batool, Zahra; Lomakin, Ivan B.; Polikanov, Yury S.; Bunick, Christopher G.

doi:10.1073/pnas.2008671117

Title: Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome

Journal Article · Wed Aug 12 00:00:00 EDT 2020 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.2008671117· OSTI ID:1657561

Batool, Zahra ^[1];

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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

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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: 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.

Grant/Contract Number:: AC02-06CH11357; K08-AR070290; R01-GM132302; R21-AI137584; P41-GM103403; S10-RR029205; S10-OD021527

OSTI ID:: 1657561

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 117, Issue 34; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
sarecycline
tetracycline
antibiotic
70S ribosome
X-ray structure

Title: Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome

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