气候变化领域集成服务门户(CCPortal): Principles for computational design of binding antibodies

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DOI	10.1073/pnas.1707171114
	Principles for computational design of binding antibodies
	Baran D.; Pszolla M.G.; Lapidoth G.D.; Norn C.; Dym O.; Unger T.; Albeck S.; Tyka M.D.; Fleishman S.J.
发表日期	2017
ISSN	0027-8424
起始页码	10900
结束页码	10905
卷号	114 期号:41
英文摘要	Natural proteins must both fold into a stable conformation and exert their molecular function. To date, computational design has successfully produced stable and atomically accurate proteins by using so-called “ideal” folds rich in regular secondary structures and almost devoid of loops and destabilizing elements, such as cavities. Molecular function, such as binding and catalysis, however, often demands nonideal features, including large and irregular loops and buried polar interaction networks, which have remained challenging for fold design. Through five design/experiment cycles, we learned principles for designing stable and functional antibody variable fragments (Fvs). Specifically, we (i) used sequence-design constraints derived from antibody multiple-sequence alignments, and (ii) during backbone design, maintained stabilizing interactions observed in natural antibodies between the framework and loops of complementarity-determining regions (CDRs) 1 and 2. Designed Fvs bound their ligands with midnanomolar affinities and were as stable as natural antibodies, despite having >30 mutations from mammalian antibody germlines. Furthermore, crystallographic analysis demonstrated atomic accuracy throughout the framework and in four of six CDRs in one design and atomic accuracy in the entire Fv in another. The principles we learned are general, and can be implemented to design other nonideal folds, generating stable, specific, and precise antibodies and enzymes. © 2017, National Academy of Sciences. All rights reserved.
英文关键词	AbDesign; Expressibility; Rosetta; Stability; V(D)J recombination
语种	英语
scopus关键词	acyl carrier protein; antibody; human insulin; unclassified drug; variable fragment antibody; acyl carrier protein acetyltransferase; antibody; immunoglobulin fragment; insulin; ligand; antigen binding; Article; binding affinity; complementarity determining region; controlled study; crystallography; molecular interaction; mutation; priority journal; protein secondary structure; sequence alignment; antibody combining site; chemistry; enzymology; human; immunology; metabolism; molecular model; Mycobacterium tuberculosis; protein conformation; X ray crystallography; Acyl-Carrier Protein S-Acetyltransferase; Antibodies; Binding Sites, Antibody; Complementarity Determining Regions; Crystallography, X-Ray; Humans; Immunoglobulin Fragments; Insulin; Ligands; Models, Molecular; Mycobacterium tuberculosis; Protein Conformation
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/160590
作者单位	Baran, D., Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 76100, Israel, IgC Bio Ltd., Ness Ziona, 7403622, Israel; Pszolla, M.G., Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 76100, Israel; Lapidoth, G.D., Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 76100, Israel; Norn, C., Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 76100, Israel, Department of Biochemistry and Structural Biology, Center for Molecular Protein Science, Lund University, Lund, SE-221 00, Sweden; Dym, O., Israeli Structural Proteomics Center, Weizmann Institute of Science, Rehovot, 76100, Israel; Unger, T., Israeli Structural Proteomics Center, Weizmann Institute of Science, Rehovot, 76100, Israel; Albeck, S., Israeli Structural Proteomics Center, Weizmann Institute of Science, Rehovot, 76100, Israel; Tyka, M.D., Google, Inc., Mountain View, CA 94043, United States; Fleishman, S.J., Department of Biomolecular Scie...
推荐引用方式 GB/T 7714	Baran D.,Pszolla M.G.,Lapidoth G.D.,et al. Principles for computational design of binding antibodies[J],2017,114(41).
APA	Baran D..,Pszolla M.G..,Lapidoth G.D..,Norn C..,Dym O..,...&Fleishman S.J..(2017).Principles for computational design of binding antibodies.Proceedings of the National Academy of Sciences of the United States of America,114(41).
MLA	Baran D.,et al."Principles for computational design of binding antibodies".Proceedings of the National Academy of Sciences of the United States of America 114.41(2017).