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

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• T cell activity is regulated by T cell receptor (TCR) signaling and immune checkpoints like PD-1, CTLA-4, and LAG-3.
• The precise mechanism of LAG-3 binding to human leukocyte antigen class II (HLA-II) molecules was previously undefined.

Purpose of the Study:

• To elucidate the structural basis of the interaction between LAG-3 and HLA-II molecules.
• To investigate the energetic contributions of the LAG-3-HLA-II complex interface.

Main Methods:

• X-ray crystallography was used to determine the structure of the LAG-3-peptide-HLA-II complex at 3.4 angstrom resolution.
• Energetic analysis was performed to probe the complex interface.

Main Results:

• LAG-3 forms a homodimer that laterally engages two HLA-II molecules via distal D1 domain surfaces, creating a 38° angular offset.
• The LAG-3-HLA-II interface is discontinuous, does not involve the D1 extra loop (a target for antibodies), and orders mobile LAG-3 loops upon binding.
• Contact residues are conserved across HLA-DR, DQ, and DP allomorphs.

Conclusions:

• The study provides the first atomic-level structural understanding of LAG-3 binding to HLA-II.
• This structural foundation is critical for designing novel immunomodulatory therapies targeting the LAG-3 pathway.