9BF9

Human LAG-3-HLA-DR1 complex

9BF9 の概要

• エントリーDOI: 10.2210/pdb9bf9/pdb
• 分子名称: HLA class II histocompatibility antigen, DR alpha chain, HLA class II histocompatibility antigen DR beta chain, Membrane protein, ... (8 entities in total)
• 機能のキーワード: immune receptor complex class ii human leucocyte antigen lymphocyte activation gene-3 immune system, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 94219.30

構造登録者

Petersen, J.,Rossjohn, J. (登録日: 2024-04-17, 公開日: 2024-12-25)

主引用文献

Petersen, J.,Llerena, C.,Golzarroshan, B.,Faoro, C.,Triebel, F.,Rossjohn, J.
Crystal structure of the human LAG-3-HLA-DR1-peptide complex.
Sci Immunol, 9:eads5122-eads5122, 2024

PubMed Abstract: 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.

PubMed: 39671469
DOI: 10.1126/sciimmunol.ads5122

実験手法

X-RAY DIFFRACTION (3.4 Å)