Structural evaluation of a nanobody targeting complement receptor Vsig4 and its cross reactivity
Structural evaluation of a nanobody targeting complement receptor Vsig4 and its cross reactivity
复制标题
靶向补体受体 Vsig4 的纳米抗体的结构评估及其交叉反应性
DOI：
10.1016/j.imbio.2016.11.008
复制
发表时间：
2017-06-01
期刊：
影响因子：
2.8
通讯作者：
Zheng, Fang
中科院分区：
文献类型：
--
作者：
Wen, Yurong;Ouyang, Zhenlin;Zheng, Fang
Vsig 4是最近鉴定的与B7家族相关的免疫调节蛋白，具有双重功能：T细胞活化的负调节因子和补体成分C3 b和C3 c的受体。在这里，我们提出了一个纳米抗体，Nb 119，对细胞外IgV结构域蛋白的小鼠和人的重组Vsig 4，具有高度的序列同一性的结构评价。尽管小鼠和人Vsig 4以250倍的解离常数差异结合Nb 119，但相互作用导致高度相同的组装，RMSD为0.4A。由Nb 119与mVsig 4和hVsig 4复合的原子结构揭示的Vsig 4识别和交叉反应性的分子决定因素为进一步优化用于人类的纳米抗体提供了新的见解。此外，Vsig 4-Nb 119复合物的结构分析表明，Nb 119占据了由C3 b的巨球蛋白样结构域MG 4和MG 5识别的Vsig 4上的界面。因此，亲和力提高的Nb 119可能具有影响T细胞和补体两者的活化的潜力。(c)2016由Elsevier GmbH出版。
Vsig4 is a recently identified immune regulatory protein related to the B7 family with dual functionality: a negative regulator of T cell activation and a receptor for the complement components C3b and C3c. Here we present a structural evaluation of a nanobody, Nb119, against the extracellular IgV domain protein of both mouse and human recombinant Vsig4, which have a high degree of sequence identity. Although mouse and human Vsig4 bind to Nb119 with a 250 times difference in dissociation constants, the interaction results in a highly identical assembly with a RMSD of 0.4A. The molecular determinants for Vsig4 recognition and cross reactivity unveiled by the atomic structure of Nb119 in complex with mVsig4 and hVsig4 afford new insights useful for the further optimization of the nanobody for potential use in humans. Additionally, structural analysis of the Vsig4-Nb119 complexes indicates that Nb119 occupies the interface on Vsig4 recognized by the macroglobulin-like domains MG4 and MG5 of C3b. Thus an affinity-improved Nb119 may have the potential to influence the activation of both T cells and complement. (c) 2016 Published by Elsevier GmbH.