7TZH

Structure of human LAG3 domains 3-4 in complex with antibody single chain-variable fragment

7TZH の概要

• エントリーDOI: 10.2210/pdb7tzh/pdb
• 分子名称: scFvF7, Lymphocyte activation gene 3 protein, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• 機能のキーワード: immune checkpoint, cell surface, t cell, complex, antibody, ig-like fold, immunosuppressant
• 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: 92020.60

構造登録者

Ming, Q.,Tran, T.H.,Luca, V.C. (登録日: 2022-02-15, 公開日: 2022-05-11, 最終更新日: 2024-11-13)

主引用文献

Ming, Q.,Celias, D.P.,Wu, C.,Cole, A.R.,Singh, S.,Mason, C.,Dong, S.,Tran, T.H.,Amarasinghe, G.K.,Ruffell, B.,Luca, V.C.
LAG3 ectodomain structure reveals functional interfaces for ligand and antibody recognition.
Nat.Immunol., 23:1031-1041, 2022

PubMed Abstract: The immune checkpoint receptor lymphocyte activation gene 3 protein (LAG3) inhibits T cell function upon binding to major histocompatibility complex class II (MHC class II) or fibrinogen-like protein 1 (FGL1). Despite the emergence of LAG3 as a target for next-generation immunotherapies, we have little information describing the molecular structure of the LAG3 protein or how it engages cellular ligands. Here we determined the structures of human and murine LAG3 ectodomains, revealing a dimeric assembly mediated by Ig domain 2. Epitope mapping indicates that a potent LAG3 antagonist antibody blocks interactions with MHC class II and FGL1 by binding to a flexible 'loop 2' region in LAG3 domain 1. We also defined the LAG3-FGL1 interface by mapping mutations onto structures of LAG3 and FGL1 and established that FGL1 cross-linking induces the formation of higher-order LAG3 oligomers. These insights can guide LAG3-based drug development and implicate ligand-mediated LAG3 clustering as a mechanism for disrupting T cell activation.

PubMed: 35761082
DOI: 10.1038/s41590-022-01238-7

実験手法

X-RAY DIFFRACTION (2.43 Å)