9CYM

Structure of LAG3 bound to the MHC class II molecule I-A(b)

Summary for 9CYM

• Entry DOI: 10.2210/pdb9cym/pdb
• Descriptor: Secreted lymphocyte activation gene 3 protein, H-2 class II histocompatibility antigen, A-B alpha chain, Class-II-associated invariant chain peptide, ... (5 entities in total)
• Functional Keywords: lag3, mhc class ii, immune checkpoint, t cell, immune system
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 4
• Total formula weight: 72936.03

Authors

Ming, Q.,Antfolk, D.,Tran, T.H.,Luca, V.C. (deposition date: 2024-08-02, release date: 2024-08-21, Last modification date: 2024-10-23)

Primary citation

Ming, Q.,Antfolk, D.,Price, D.A.,Manturova, A.,Medina, E.,Singh, S.,Mason, C.,Tran, T.H.,Smalley, K.S.M.,Leung, D.W.,Luca, V.C.
Structural basis for mouse LAG3 interactions with the MHC class II molecule I-A b.
Nat Commun, 15:7513-7513, 2024

PubMed Abstract: The immune checkpoint protein, Lymphocyte activation gene-3 (LAG3), binds Major Histocompatibility Complex Class II (MHC-II) and suppresses T cell activation. Despite the recent FDA approval of a LAG3 inhibitor for the treatment of melanoma, how LAG3 engages MHC-II on the cell surface remains poorly understood. Here, we determine the 3.84 Å-resolution structure of mouse LAG3 bound to the MHC-II molecule I-A, revealing that domain 1 (D1) of LAG3 binds a conserved, membrane-proximal region of MHC-II spanning both the α2 and β2 subdomains. LAG3 dimerization restricts the intermolecular spacing of MHC-II molecules, which may attenuate T cell activation by enforcing suboptimal signaling geometry. The LAG3-MHC-II interface overlaps with the MHC-II-binding site of the T cell coreceptor CD4, implicating disruption of CD4-MHC-II interactions as a mechanism for LAG3 immunosuppressive function. Lastly, antibody epitope analysis indicates that multiple LAG3 inhibitors do not recognize the MHC-II-binding interface of LAG3, suggesting a role for functionally distinct mechanisms of LAG3 antagonism in therapeutic development.

PubMed: 39209860
DOI: 10.1038/s41467-024-51930-5

Experimental method

X-RAY DIFFRACTION (3.84 Å)