Crystal structure of the human LAG-3–HLA-DR1–peptide complex

Petersen, Jan, Llerena, Carmen, Golzarroshan, Bagher, Faoro, Camilla, Triebel, Frederic and Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 2024. Crystal structure of the human LAG-3–HLA-DR1–peptide complex. Science Immunology 9 (102) , eads5122. 10.1126/sciimmunol.ads5122

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	American Association for the Advancement of Science
ISSN:	2470-9468
Date of First Compliant Deposit:	7 March 2025
Date of Acceptance:	15 November 2024
Last Modified:	07 Mar 2025 11:15
URI:	https://orca.cardiff.ac.uk/id/eprint/175093

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