气候变化领域集成服务门户(CCPortal): Charting the sequence-activity landscape of peptide inhibitors of translation termination

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DOI	10.1073/pnas.2026465118
	Charting the sequence-activity landscape of peptide inhibitors of translation termination
	Baliga C.; Brown T.J.; Florin T.; Colon S.; Shah V.; Skowron K.J.; Kefi A.; Szal T.; Klepacki D.; Moore T.W.; Vázquez-Laslop N.; Mankin A.S.
发表日期	2021
ISSN	00278424
卷号	118 期号:10
英文摘要	Apidaecin (Api), an unmodified 18-amino-acid-long proline-rich antibacterial peptide produced by bees, has been recently described as a specific inhibitor of translation termination. It invades the nascent peptide exit tunnel of the postrelease ribosome and traps the release factors preventing their recycling. Api binds in the exit tunnel in an extended conformation that matches the placement of a nascent polypeptide and establishes multiple contacts with ribosomal RNA (rRNA) and ribosomal proteins. Which of these interactions are critical for Api’s activity is unknown. We addressed this problem by analyzing the activity of all possible single-amino-acid substitutions of the Api variants synthesized in the bacterial cell. By conditionally expressing the engineered api gene, we generated Api directly in the bacterial cytosol, thereby bypassing the need for importing the peptide from the medium. The endogenously expressed Api, as well as its N-terminally truncated mutants, retained the antibacterial properties and the mechanism of action of the native peptide. Taking advantage of the Api expression system and next-generation sequencing, we mapped in one experiment all the single-amino-acid substitutions that preserve or alleviate the on-target activity of the Api mutants. Analysis of the inactivating mutations made it possible to define the pharmacophore of Api involved in critical interactions with the ribosome, transfer RNA (tRNA), and release factors. We also identified the Api segment that tolerates a variety of amino acid substitutions; alterations in this segment could be used to improve the pharmacological properties of the antibacterial peptide. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Antibiotic; Apidaecin; Nascent peptide exit tunnel; Ribosome; Translation termination
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180328
作者单位	Center for Biomolecular Sciences, University of Illinois, Chicago, IL 60607, United States; Department of Pharmaceutical Sciences, University of Illinois, Chicago, IL 60607, United States
推荐引用方式 GB/T 7714	Baliga C.,Brown T.J.,Florin T.,et al. Charting the sequence-activity landscape of peptide inhibitors of translation termination[J],2021,118(10).
APA	Baliga C..,Brown T.J..,Florin T..,Colon S..,Shah V..,...&Mankin A.S..(2021).Charting the sequence-activity landscape of peptide inhibitors of translation termination.Proceedings of the National Academy of Sciences of the United States of America,118(10).
MLA	Baliga C.,et al."Charting the sequence-activity landscape of peptide inhibitors of translation termination".Proceedings of the National Academy of Sciences of the United States of America 118.10(2021).