PDF(Pubmed)
Abstract：
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 (VL) and heavy (VH) domains, both of which present analogous complementarity-determining region (CDR) loops. It has long been known that the VH 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 VL 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 VL 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.
摘要：
抗体,通过它们靶向几乎任何表位的能力，在驱动颌骨脊椎动物的适应性免疫反应中起关键作用。标准抗体的结合域是它们的可变轻（VL）和重（VH）域，两者都存在类似的互补决定区(CDR)环。早就知道VHCDR对抗原结合表面（互补位）的贡献更大，CDR-H3环提供了产生不同互补位的主要方式。这里,我们提供了VL结构域作为CDR-H3结构调节剂的额外作用的证据，使用一组不同的抗体晶体结构和大量的分子动力学模拟。我们展示了VL域的特定属性，如子类型，CDR规范形式和基因可以影响CDR-H3环的结构多样性，并提供了一个物理模型，说明这种效应是如何通过环间接触和CDR相互包装而发生的。我们的结果表明，刚性次要环微调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。并提供对CDR构象相互依存性质的见解，了解这一点对于合理的抗体设计过程很重要。
