5NBI

Principles for computational design of antibodies

5NBI の概要

• エントリーDOI: 10.2210/pdb5nbi/pdb
• 分子名称: Design of antibodies (3 entities in total)
• 機能のキーワード: antibodies, immune system
• 由来する生物種: synthetic construct; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 48894.49

構造登録者

Dym, O.,Fleishman, S.J. (登録日: 2017-03-02, 公開日: 2017-09-27, 最終更新日: 2024-10-16)

主引用文献

Baran, D.,Pszolla, M.G.,Lapidoth, G.D.,Norn, C.,Dym, O.,Unger, T.,Albeck, S.,Tyka, M.D.,Fleishman, S.J.
Principles for computational design of binding antibodies.
Proc. Natl. Acad. Sci. U.S.A., 114:10900-10905, 2017

PubMed Abstract: 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 () used sequence-design constraints derived from antibody multiple-sequence alignments, and () 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.

PubMed: 28973872
DOI: 10.1073/pnas.1707171114

実験手法

X-RAY DIFFRACTION (2.1 Å)