Ribosome protection by antibiotic resistance ATP-binding cassette protein
| Autor: | Yichen Ding, Weixin Su, Liang Yang, Andrew S.W. Wong, Veerendra Kumar, Siu Kwan Sze, Rya Ero, Aida Serra, Jian Shi, Yong-Gui Gao, Benjamin Sian Teck Lee |
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| Přispěvatelé: | School of Biological Sciences, Institute of Structural Biology, Singapore Centre for Environmental Life Sciences and Engineering |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine antibiotic resistance protein synthesis Protein Conformation medicine.drug_class 030106 microbiology Antibiotics ribosome protection Peptide Crystallography X-Ray Biochemistry Ribosome 03 medical and health sciences Adenosine Triphosphate Antibiotic resistance Bacterial Proteins MsrE medicine Protein biosynthesis chemistry.chemical_classification Binding Sites Multidisciplinary Bacteria Biological sciences [Science] Drug Resistance Microbial Biological Sciences Ribosomal RNA Anti-Bacterial Agents ABC-F chemistry Protein Biosynthesis Antibiotic Resistance Peptidyl Transferases ATP-Binding Cassette Transporters ATP-binding cassette protein Ribosomes Linker Ribosome Protection |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| Popis: | Significance ARE ABC-F genes have been found in numerous pathogen genomes and multi-drug resistance conferring plasmids. Further transmission will challenge the clinical use of many antibiotics. The development of improved ribosome-targeting therapeutics relies on the elucidation of the resistance mechanisms. Characterization of MsrE protein bound to the bacterial ribosome is first of its kind for ARE ABC-F members. Together with biochemical data, it sheds light on the ribosome protection mechanism by domain linker-mediated conformational change and displacement leading to drug release, suggesting a mechanism shared by other ARE ABC-F proteins. These proteins present an intriguing example of structure-function relationship and a medically relevant target of study as they collectively mediate resistance to the majority of antibiotic classes targeting the peptidyl-transferase center region. 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. |
| Databáze: | OpenAIRE |
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