气候变化领域集成服务门户(CCPortal): Computationally designed peptide macrocycle inhibitors of New Delhi metallo-β-lactamase 1

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DOI	10.1073/pnas.2012800118
	Computationally designed peptide macrocycle inhibitors of New Delhi metallo-β-lactamase 1
	Mulligan V.K.; Workman S.; Sun T.; Rettie S.; Li X.; Worrall L.J.; Craven T.W.; King D.T.; Hosseinzadeh P.; Watkins A.M.; Douglas Renfrew P.; Guffy S.; Labonte J.W.; Moretti R.; Bonneau R.; Strynadka N.C.J.; Baker D.
发表日期	2021
ISSN	00278424
卷号	118 期号:12
英文摘要	The rise of antibiotic resistance calls for new therapeutics targeting resistance factors such as the New Delhi metallo-β-lactamase 1 (NDM-1), a bacterial enzyme that degrades β-lactam antibiotics. We present structure-guided computational methods for designing peptide macrocycles built from mixtures of L- and D-amino acids that are able to bind to and inhibit targets of therapeutic interest. Our methods explicitly consider the propensity of a peptide to favor a binding-competent conformation, which we found to predict rank order of experimentally observed IC50 values across seven designed NDM-1- inhibiting peptides. We were able to determine X-ray crystal structures of three of the designed inhibitors in complex with NDM-1, and in all three the conformation of the peptide is very close to the computationally designed model. In two of the three structures, the binding mode with NDM-1 is also very similar to the design model, while in the third, we observed an alternative binding mode likely arising from internal symmetry in the shape of the design combined with flexibility of the target. Although challenges remain in robustly predicting target backbone changes, binding mode, and the effects of mutations on binding affinity, our methods for designing ordered, binding-competent macrocycles should have broad applicability to a wide range of therapeutic targets. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Antibiotic resistance \| drug design \| protein folding \| peptide macrocycles \| computational design
语种	英语
scopus关键词	bacterial enzyme; New Delhi metallo beta lactamase 1; unclassified drug; Article; controlled study; crystal structure; enzyme active site; enzyme binding; enzyme conformation; enzyme inhibition assay; IC50; nonhuman; prediction; priority journal; protein targeting; X ray crystallography
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/180126
作者单位	Center for Computational Biology, Flatiron Institute, New York, NY 10010, United States; Institute for Protein Design, Department of Biochemistry, MolecularEngineering and Sciences, University of Washington, Seattle, WA 98195, United States; Department of Biochemistry and Molecular Biology, Centre for BloodResearch, University of British Columbia, Life Sciences Centre, Vancouver, BC V6T 1Z3, Canada; Department of Biochemistry, Stanford University School ofMedicine, Stanford, CA 94305, United States; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, United States; Department of Chemistry, Franklin & Marshall College, Lancaster, PA 17604, United States; Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, United States; Center for Structural Biology, Department of Chemistry, Vanderbilt University, Nashville, TN 37240, United States; Center for Genomics and Systems Biology, Departmentof Biology, New York Univer...
推荐引用方式 GB/T 7714	Mulligan V.K.,Workman S.,Sun T.,et al. Computationally designed peptide macrocycle inhibitors of New Delhi metallo-β-lactamase 1[J],2021,118(12).
APA	Mulligan V.K..,Workman S..,Sun T..,Rettie S..,Li X..,...&Baker D..(2021).Computationally designed peptide macrocycle inhibitors of New Delhi metallo-β-lactamase 1.Proceedings of the National Academy of Sciences of the United States of America,118(12).
MLA	Mulligan V.K.,et al."Computationally designed peptide macrocycle inhibitors of New Delhi metallo-β-lactamase 1".Proceedings of the National Academy of Sciences of the United States of America 118.12(2021).