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

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 leuk...

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Bibliographic Details
Published in:Science immunology 2024-12, Vol.9 (102), p.eads5122
Main Authors: Petersen, Jan, Llerena, Carmen, Golzarroshan, Bagher, Faoro, Camilla, Triebel, Frederic, Rossjohn, Jamie
Format: Article
Language:English
Subjects:
Antigens, CD - chemistry
Antigens, CD - immunology
Antigens, CD - metabolism
Crystallography, X-Ray
HLA-DR1 Antigen - chemistry
HLA-DR1 Antigen - immunology
Humans
Lymphocyte Activation Gene 3 Protein
Models, Molecular
Peptides - chemistry
Peptides - immunology
Protein Binding
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Summary: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.
ISSN:2470-9468