Talk abstracts
Talk on Friday 03:30-03:45pm submitted by Zahra Batool
Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome in a context dependent manner
Zahra Batool (Department of Biolgical Sciences, University of Illinois at Chicago), Ivan B. Lomakin (Department of Molecular Biophysics and Biochemistry, Yale University), Yury S. Polikanov (Department of Biolgical Sciences, University of Illinois at Chicago), Christopher G. Bunick (Department of Molecular Biophysics and Biochemistry, Yale University)
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. Following up on these observations, ribosome profiling analysis also showed strong context dependent inhibition at the start codon. Overall, our structural and biochemical findings rationalize the role of the unique C7 moiety of sarecycline in antibiotic action.
References:
Batool Z., Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome, PNAS, 2020
Keywords: sarecycline, ribosome, antibiotic