Guloglu Bora, Deane Charlotte M
Oxford Protein Informatics Group, Department of Statistics, University of Oxford, Oxford, United Kingdom.
Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
Front Immunol. 2023 Jul 26;14:1223802. doi: 10.3389/fimmu.2023.1223802. eCollection 2023.
Antibodies, through their ability to target virtually any epitope, play a key role in driving the adaptive immune response in jawed vertebrates. The binding domains of standard antibodies are their variable light (V) and heavy (V) domains, both of which present analogous complementarity-determining region (CDR) loops. It has long been known that the V CDRs contribute more heavily to the antigen-binding surface (paratope), with the CDR-H3 loop providing a major modality for the generation of diverse paratopes. Here, we provide evidence for an additional role of the V domain as a modulator of CDR-H3 structure, using a diverse set of antibody crystal structures and a large set of molecular dynamics simulations. We show that specific attributes of the V domain such as subtypes, CDR canonical forms and genes can influence the structural diversity of the CDR-H3 loop, and provide a physical model for how this effect occurs through inter-loop contacts and packing of CDRs against each other. Our results indicate that the rigid minor loops fine-tune the structure of CDR-H3, thereby contributing to the generation of surfaces complementary to the vast number of possible epitope topologies, and provide insights into the interdependent nature of CDR conformations, an understanding of which is important for the rational antibody design process.
抗体能够靶向几乎任何表位，在颌口脊椎动物适应性免疫反应中发挥关键作用。标准抗体的结合域是其可变轻链（V）和重链（V）结构域，二者均具有类似的互补决定区（CDR）环。长期以来，人们已知V CDR对抗原结合表面（互补位）的贡献更大，其中CDR-H3环为多种互补位的产生提供了主要方式。在此，我们利用一系列多样的抗体晶体结构和大量分子动力学模拟，为V结构域作为CDR-H3结构调节剂的额外作用提供了证据。我们表明，V结构域的特定属性，如亚型、CDR规范形式和基因，可影响CDR-H3环的结构多样性，并提供了一个物理模型，解释这种效应如何通过环间接触以及CDR相互堆积而发生。我们的结果表明，刚性小环微调CDR-H3的结构，从而有助于产生与大量可能的表位拓扑互补的表面，并为CDR构象的相互依存性质提供了见解，理解这一点对于合理的抗体设计过程很重要。
