Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 20, Pages 5157-5162Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1803313115
Keywords
ribosome protection; antibiotic resistance; ABC-F; MsrE; protein synthesis
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Funding
- Singapore National Research Foundation [NRF-RF2009-RF001-267]
- Ministry of Education of Singapore [MOE2014-T2-1-083, MOE2017-T2-1-106, MOE2016-T2-1-010]
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The ribosome is one of the richest targets for antibiotics. Unfortunately, antibiotic resistance is an urgent issue in clinical practice. Several ATP-binding cassette family proteins confer resistance to ribosome-targeting antibiotics through a yet unknown mechanism. Among them, MsrE has been implicated in macrolide resistance. Here, we report the cryo-EM structure of ATP form MsrE bound to the ribosome. Unlike previously characterized ribosomal protection proteins, MsrE is shown to bind to ribosomal exit site. Our structure reveals that the domain linker forms a unique needle-like arrangement with two crossed helices connected by an extended loop projecting into the peptidyl-transferase center and the nascent peptide exit tunnel, where numerous antibiotics bind. In combination with biochemical assays, our structure provides insight into how MsrE binding leads to conformational changes, which results in the release of the drug. This mechanism appears to be universal for the ABC-F type ribosome protection proteins.
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