globalchange  > 气候变化与战略
DOI: 10.1073/pnas.1707171114
论文题名:
Principles for computational design of binding antibodies
作者: Baran D.; Pszolla M.G.; Lapidoth G.D.; Norn C.; Dym O.; Unger T.; Albeck S.; Tyka M.D.; Fleishman S.J.
刊名: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
出版年: 2017
卷: 114, 期:41
起始页码: 10900
结束页码: 10905
语种: 英语
英文关键词: AbDesign ; Expressibility ; Rosetta ; Stability ; V(D)J recombination
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
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.
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资源类型: 期刊论文
标识符: http://119.78.100.158/handle/2HF3EXSE/163790
Appears in Collections:气候变化与战略

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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 Sciences, Weizmann Institute of Science, Rehovot, 76100, Israel

Recommended Citation:
Baran D.,Pszolla M.G.,Lapidoth G.D.,et al. Principles for computational design of binding antibodies[J]. Proceedings of the National Academy of Sciences of the United States of America,2017-01-01,114(41)
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