Structural basis of the therapeutic anti-PD-L1 antibody atezolizumab.
Structural basis of the therapeutic anti-PD-L1 antibody atezolizumab.
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治疗性抗 PD-L1 抗体 atezolizumab 的结构基础
DOI：
10.18632/oncotarget.21652
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发表时间：
2017-10-27
期刊：
影响因子：
--
通讯作者：
Zheng Y
中科院分区：
文献类型：
--
作者：
Zhang F;Qi X;Wang X;Wei D;Wu J;Feng L;Cai H;Wang Y;Zeng N;Xu T;Zhou A;Zheng Y
靶向PD-1/PD-L1信号通路的单克隆抗体在过去几年中在癌症治疗中取得了前所未有的成功。Atezolizumab是美国FDA批准用于癌症治疗的第一个PD-L1单克隆抗体;然而，Atezolizumab阻断PD-1/PD-L1相互作用的分子基础尚未完全了解。在此，我们以2.9埃分辨率解析了PD-L1/atezolizumab复合物的晶体结构。结构显示atezolizumab通过重链的3个CDR环和轻链的1个CDR环与PD-L1的前β折叠结合。结合涉及广泛的氢键和疏水相互作用。值得注意的是，存在来自CDR环的多个芳香族残基，在结合界面的中心内形成Pi-Pi堆叠或阳离子-Pi相互作用，并且掩埋表面积大于2000 μ 2，这是所有已知的PD-L1/抗体结构中最大的。突变研究显示，PD-L1的两个热点残基（E58、R113）对atezolizumab的结合有显著贡献。该结构还表明atezolizumab以不同的重链和轻链方向结合PD-L1，并通过与PD-1竞争相同的PD-L1表面积来阻断PD-1/PD-L1相互作用。综上所述，本文解出的PD-L1/atezolizumab复合物结构揭示了atezolizumab在免疫治疗中的分子机制，为今后单克隆抗体优化和靶向PD-L1表面的小分子化合物的合理设计提供了基础。
Monoclonal antibodies targeting PD-1/PD-L1 signaling pathway have achieved unprecedented success in cancer treatment over the last few years. Atezolizumab is the first PD-L1 monoclonal antibody approved by US FDA for cancer therapy; however the molecular basis of atezolizumab in blocking PD-1/PD-L1 interaction is not fully understood. Here we have solved the crystal structure of PD-L1/atezolizumab complex at 2.9 angstrom resolution. The structure shows that atezolizumab binds the front beta-sheet of PD-L1 through three CDR loops from the heavy chain and one CDR loop from the light chain. The binding involves extensive hydrogen-bonding and hydrophobic interactions. Notably there are multiple aromatic residues from the CDR loops forming Pi-Pi stacking or cation-Pi interactions within the center of the binding interface and the buried surface area is more than 2000 Å2, which is the largest amongst all the known PD-L1/antibody structures. Mutagenesis study revealed that two hot-spot residues (E58, R113) of PD-L1 contribute significantly to the binding of atezolizumab. The structure also shows that atezolizumab binds PD-L1 with a distinct heavy and light chain orientation and it blocks PD-1/PD-L1 interaction through competing with PD-1 for the same PD-L1 surface area. Taken together, the complex structure of PD-L1/atezolizumab solved here revealed the molecular mechanism of atezolizumab in immunotherapy and provides basis for future monoclonal antibody optimization and rational design of small chemical compounds targeting PD-L1 surface.
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DOI：
10.1038/nri3405
发表时间：
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期刊：
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10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
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作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
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