Nascent peptide assists the ribosome in recognizing chemically distinct small molecules

Gupta, Pulkit; Liu, Bo; Klepacki, Dorota; Gupta, Vrinda; Schulten, Klaus; Mankin, Alexander S.; Vázquez-Laslop, Nora

doi:10.1038/nchembio.1998

Title: Nascent peptide assists the ribosome in recognizing chemically distinct small molecules

Journal Article · Mon Jan 04 00:00:00 EST 2016 · Nature Chemical Biology

DOI:https://doi.org/10.1038/nchembio.1998· OSTI ID:1565455

Gupta, Pulkit; Liu, Bo; Klepacki, Dorota; Gupta, Vrinda; Schulten, Klaus; Mankin, Alexander S.;

Regulation of gene expression in response to the changing environment is critical for cell survival. For instance, binding of macrolide antibiotics to the ribosome promotes translation arrest at the leader open reading frames ermCL and ermBL, which is necessary for inducing the antibiotic resistance genes ermC and ermB. Cladinose-containing macrolides such as erythromycin (ERY), but not ketolides such as telithromycin (TEL), arrest translation of ermCL, whereas either ERY or TEL stall ermBL translation. How the ribosome distinguishes between chemically similar small molecules is unknown. We show that single amino acid changes in the leader peptide switch the specificity of recognition of distinct molecules, triggering gene activation in response to ERY alone, to TEL alone or to both antibiotics or preventing stalling altogether. Thus, the ribosomal response to chemical signals can be modulated by minute changes in the nascent peptide, suggesting that protein sequences could have been optimized for rendering translation sensitive to environmental cues.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)

Sponsoring Organization:: USDOE Office of Science (SC)

DOE Contract Number:: AC05-00OR22725

OSTI ID:: 1565455

Journal Information:: Nature Chemical Biology, Vol. 12, Issue 3; ISSN 1552-4450

Publisher:: Nature Publishing Group

Country of Publication:: United States

Language:: English

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