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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