6UMT

High-affinity human PD-1 PD-L2 complex

6UMT の概要

• エントリーDOI: 10.2210/pdb6umt/pdb
• 分子名称: Programmed cell death protein 1, Programmed cell death 1 ligand 2, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: pd-1, pd-l2, immune checkpoint, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 29402.68

構造登録者

Tang, S.,Kim, P.S. (登録日: 2019-10-10, 公開日: 2019-11-27, 最終更新日: 2024-10-23)

主引用文献

Tang, S.,Kim, P.S.
A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery.
Proc.Natl.Acad.Sci.USA, 116:24500-24506, 2019

PubMed Abstract: Immune checkpoint blockade of programmed death-1 (PD-1) by monoclonal antibody drugs has delivered breakthroughs in the treatment of cancer. Nonetheless, small-molecule PD-1 inhibitors could lead to increases in treatment efficacy, safety, and global access. While the ligand-binding surface of apo-PD-1 is relatively flat, it harbors a striking pocket in the murine PD-1/PD-L2 structure. An analogous pocket in human PD-1 may serve as a small-molecule drug target, but the structure of the human complex is unknown. Because the CC' and FG loops in murine PD-1 adopt new conformations upon binding PD-L2, we hypothesized that mutations in these two loops could be coupled to pocket formation and alter PD-1's affinity for PD-L2. Here, we conducted deep mutational scanning in these loops and used yeast surface display to select for enhanced PD-L2 binding. A PD-1 variant with three substitutions binds PD-L2 with an affinity two orders of magnitude higher than that of the wild-type protein, permitting crystallization of the complex. We determined the X-ray crystal structures of the human triple-mutant PD-1/PD-L2 complex and the apo triple-mutant PD-1 variant at 2.0 Å and 1.2 Å resolution, respectively. Binding of PD-L2 is accompanied by formation of a prominent pocket in human PD-1, as well as substantial conformational changes in the CC' and FG loops. The structure of the apo triple-mutant PD-1 shows that the CC' loop adopts the ligand-bound conformation, providing support for allostery between the loop and pocket. This human PD-1/PD-L2 structure provide critical insights for the design and discovery of small-molecule PD-1 inhibitors.

PubMed: 31727844
DOI: 10.1073/pnas.1916916116

実験手法

X-RAY DIFFRACTION (1.986 Å)