抗体 CDR 环在结合时会改变构象吗?

IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
mAbs Pub Date : 2024-01-01 Epub Date: 2024-03-13 DOI:10.1080/19420862.2024.2322533
Chu'nan Liu, Lilian M Denzler, Oliver E C Hood, Andrew C R Martin
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引用次数: 0

摘要

抗体越来越多地被开发成药物,目前已有 100 多种抗体在美国或欧盟获得许可。在开发过程中,经常需要提高或降低抗体的亲和力,而要做到这一点,合理的尝试依赖于通常通过建模获得的抗体-抗原复合物的结构。抗原结合位点主要由六个称为互补决定区(CDR)的环路组成,而这些环路在与抗原结合时是否会改变其构象一直是个悬而未决的问题。现有的抗体-抗原复合物结构调查只在个案研究或小规模调查中研究 CDR 的构象变化。随着越来越多的抗体的自由结构和复合物结构被存入蛋白质数据库,对结合过程中CDR构象变化的大规模调查现在成为可能。为此,我们建立了一个数据集 AbAgDb,目前包括 177 种具有高质量 CDR 的抗体,每种抗体至少有一种结合结构和一种非结合结构。我们分析了每个 CDR 的 Cα 主干在结合时的构象变化,发现在大多数情况下,CDR(CDR-H3 除外)的移动极小,而 70.6% 和 87% 的 CDR-H3 的全局 Cα RMSD 分别≤ 1.0Å 和≤ 2.0Å。我们还将结合的 CDR 构象与未结合 CDR 的构象空间进行了比较,发现大部分结合构象都包含在未结合构象空间中。今后,我们的研究结果将有助于深入了解抗体以及建模和对接的新方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Do antibody CDR loops change conformation upon binding?

Antibodies have increasingly been developed as drugs with over 100 now licensed in the US or EU. During development, it is often necessary to increase or reduce the affinity of an antibody and rational attempts to do so rely on having a structure of the antibody-antigen complex often obtained by modeling. The antigen-binding site consists primarily of six loops known as complementarity-determining regions (CDRs), and an open question has been whether these loops change their conformation when they bind to an antigen. Existing surveys of antibody-antigen complex structures have only examined CDR conformational change in case studies or small-scale surveys. With an increasing number of antibodies where both free and complexed structures have been deposited in the Protein Data Bank, a large-scale survey of CDR conformational change during binding is now possible. To this end, we built a dataset, AbAgDb, that currently includes 177 antibodies with high-quality CDRs, each of which has at least one bound and one unbound structure. We analyzed the conformational change of the Cα backbone of each CDR upon binding and found that, in most cases, the CDRs (other than CDR-H3) show minimal movement, while 70.6% and 87% of CDR-H3s showed global Cα RMSD ≤ 1.0Å and ≤ 2.0Å, respectively. We also compared bound CDR conformations with the conformational space of unbound CDRs and found most of the bound conformations are included in the unbound conformational space. In future, our results will contribute to developing insights into antibodies and new methods for modeling and docking.

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来源期刊
mAbs
mAbs 工程技术-仪器仪表
CiteScore
10.70
自引率
11.30%
发文量
77
审稿时长
6-12 weeks
期刊介绍: mAbs is a multi-disciplinary journal dedicated to the art and science of antibody research and development. The journal has a strong scientific and medical focus, but also strives to serve a broader readership. The articles are thus of interest to scientists, clinical researchers, and physicians, as well as the wider mAb community, including our readers involved in technology transfer, legal issues, investment, strategic planning and the regulation of therapeutics.
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