T cell activity is governed by T cell receptor (TCR) signaling and constrained by immune checkpoint molecules, including programmed cell death protein 1 (PD-1), cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), and lymphocyte activation gene 3 (LAG-3). The basis for how LAG-3 binds to human leukocyte antigen class II molecules (HLA-II) remains unknown. Here, we present the 3.4-angstrom crystal structure of a LAG-3–peptide–HLA-II complex and probe the energetics of the complex interface. Coincident with the HLA-II binding site of the ancestrally related, monomeric CD4 receptor, the LAG-3 homodimer laterally engages two HLA-II molecules via distal D1 domain surfaces, imposing a 38° angular offset. The LAG-3–HLA-II interface is discontinuous and lacks involvement of the D1 extra loop, a binding site for anti–LAG-3 therapeutic monoclonal antibodies. Upon HLA-II binding, intrinsically mobile loops of the LAG-3 molecule become ordered, with contact residues highly conserved across HLA-DR, DQ, and DP allomorphs. Our data provide a structural foundation for development of immunomodulatory approaches targeting LAG-3.

中文翻译：

---

人 LAG-3-HLA-DR1-肽复合物的晶体结构


T 细胞活性受 T 细胞受体 （TCR） 信号转导控制，并受免疫检查点分子限制，包括程序性细胞死亡蛋白 1 （PD-1）、细胞毒性 T 淋巴细胞相关抗原 4 （CTLA-4） 和淋巴细胞活化基因 3 （LAG-3）。LAG-3 如何与人类白细胞抗原 II 类分子 （HLA-II） 结合的基础仍然未知。在这里，我们介绍了 LAG-3-肽-HLA-II 复合物的 3.4 埃晶体结构，并探索了复合物界面的能量学。与祖先相关的单体 CD4 受体的 HLA-II 结合位点重合，LAG-3 同源二聚体通过远端 D1 结构域表面横向接合两个 HLA-II 分子，施加 38° 的角度偏移。LAG-3-HLA-II 界面是不连续的，并且没有 D1 额外环的参与，D1 额外环是抗 LAG-3 治疗性单克隆抗体的结合位点。HLA-II 结合后，LAG-3 分子的内在移动环变得有序，接触残基在 HLA-DR、DQ 和 DP 同种异型中高度保守。我们的数据为开发靶向 LAG-3 的免疫调节方法提供了结构基础。