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首页> 外文期刊>Journal of Molecular Biology >Evidence for structural plasticity of heavy chain complementarity-determining region 3 in antibody-ssDNA recognition
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Evidence for structural plasticity of heavy chain complementarity-determining region 3 in antibody-ssDNA recognition

机译：抗体-ssDNA识别中重链互补决定区3结构可塑性的证据

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Anti-DNA antibodies play important roles in the pathogenesis of autoimmune diseases. They also represent a unique and relatively unexplored class of DNA-binding protein. Here, we present a study of conformational changes induced by DNA binding to an anti-ssDNA Fab known as DNA-1. Three crystal structures are reported: a complex of DNA-1 bound to dT(3), and two structures of the ligand-free Fab. One of the ligand-free structures was determined from crystals exhibiting perfect hemihedral twinning, and the details of structure determination are,, provided. Unexpectedly, five residues (H97-H100A) in the apex of heavy chain complementarity-determining region 3 (HCDR3) are disordered in both ligand-free structures. Ligand binding also caused a 2-4 A shift of the backbone of Tyr L92 and ordering of the L92 side-chain. In contrast, these residues are highly ordered in the Fab/dT(3) complex, where Tyr H100 and Tyr H100A form intimate stacking interactions with DNA bases, and L92 forms the 5' end of the binding site. The structures suggest that HCDR3 is very flexible and adopts multiple conformations in the ligand-free state. These results are discussed in terms of induced fit and pre-existing equilibrium theories of ligand binding. Our results allow new interpretations of existing thermodynamic and mutagenesis data in terms of conformational entropy and the volume of conformational space accessible to HCDR3 in the ligand-free state. In the context of autoimmune disease, plasticity of the ligand-free antibody could provide a mechanism by which anti-DNA antibodies bind diverse host ligands, and thereby contribute to pathogenicity. (c) 2005 Elsevier Ltd. All rights reserved.
机译：抗DNA抗体在自身免疫性疾病的发病机理中起着重要作用。它们还代表了独特的且相对未开发的一类DNA结合蛋白。在这里，我们介绍了一种由DNA结合到称为DNA-1的抗ssDNA Fab诱导的构象变化的研究。报告了三个晶体结构：绑定到dT（3）的DNA-1的复合物和无配体的Fab的两个结构。由表现出完美的半面孪晶的晶体确定无配体的结构之一，并提供确定结构的细节。出乎意料的是，重链互补决定区3（HCDR3）的顶点中的五个残基（H97-H100A）在两个无配体的结构中均无序。配体结合还引起Tyr L92主链的2-4 A移位和L92侧链的有序化。相反，这些残基在Fab / dT（3）复合物中是高度有序的，其中Tyr H100和Tyr H100A与DNA碱基形成紧密的堆叠相互作用，而L92形成结合位点的5'末端。该结构表明，HCDR3非常灵活，并在无配体状态下采用多种构象。这些结果将根据诱导配体和配体结合的平衡理论进行讨论。我们的结果允许对现有的热力学和诱变数据进行新的解释，包括构象熵和无配体状态下HCDR3可获得的构象空间量。在自身免疫疾病的情况下，不含配体的抗体的可塑性可以提供一种机制，通过这种机制，抗DNA抗体可以结合各种宿主配体，从而促进致病性。 （c）2005 Elsevier Ltd.保留所有权利。

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