2. Academic Validation
  3. Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome

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

  • Proc Natl Acad Sci U S A. 2020 Aug 25;117(34):20530-20537. doi: 10.1073/pnas.2008671117.
Zahra Batool 1,  Ivan B Lomakin 2 3,  Yury S Polikanov 4 5 6,  Christopher G Bunick 7 3
Affiliations

Affiliations

  • 1 Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607.
  • 2 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520.
  • 3 Department of Dermatology, Yale University, New Haven, CT 06520.
  • 4 Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607; yuryp@uic.edu christopher.bunick@yale.edu.
  • 5 Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL 60607.
  • 6 Center for Biomolecular Sciences, University of Illinois at Chicago, Chicago, IL 60607.
  • 7 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520; yuryp@uic.edu christopher.bunick@yale.edu.
PMID: 32817463 DOI: 10.1073/pnas.2008671117
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.

Keywords

70S ribosome; X-ray structure; antibiotic; sarecycline; tetracycline.

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