Structure of the Complex of Human Programmed Death 1, PD-1, and Its Ligand PD-L1.
Structure of the Complex of Human Programmed Death 1, PD-1, and Its Ligand PD-L1.
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DOI：
10.1016/j.str.2015.09.010
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发表时间：
2015-12-01
期刊：
影响因子：
--
通讯作者：
Holak TA
中科院分区：
文献类型：
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作者：
Zak KM;Kitel R;Przetocka S;Golik P;Guzik K;Musielak B;Dömling A;Dubin G;Holak TA
最近，以PD-1/PD-L1免疫检查点为靶点的单抗在治疗黑色素瘤、非小细胞肺癌和其他类型癌症方面取得了突破性进展。干扰这一途径的小分子药物备受期待，但结构信息不足阻碍了它们的发展。本研究基于络合物的X射线结构揭示了人类PD-1/PD-L1相互作用的分子细节。首先，研究表明，与人PD-1结合的配体与受体内显著的可塑性有关。其次，提供了相互作用表面的详细分子图，允许定义两个相互作用伙伴内可能成为小分子靶标的区域。
Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has recently provided breakthrough progress in the treatment of melanoma, non-small cell lung cancer, and other types of cancer. Small-molecule drugs interfering with this pathway are highly awaited, but their development is hindered by insufficient structural information. This study reveals the molecular details of the human PD-1/PD-L1 interaction based on an X-ray structure of the complex. First, it is shown that the ligand binding to human PD-1 is associated with significant plasticity within the receptor. Second, a detailed molecular map of the interaction surface is provided, allowing definition of the regions within both interacting partners that may likely be targeted by small molecules.