8DGG

Structure of glycosylated LAG-3 homodimer

Summary for 8DGG

• Entry DOI: 10.2210/pdb8dgg/pdb
• Descriptor: Lymphocyte activation gene 3 protein, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: immune checkpoint receptor, homodimer, glycosylation, immune system
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 95147.97

Authors

Silberstein, J.L.,Mathews, I.I.,Frank, J.A.,Chan, K.-W.,Fernandez, D.,Du, J.,Wang, J.,Kong, X.-P.,Cochran, J.R. (deposition date: 2022-06-23, release date: 2022-08-17, Last modification date: 2024-08-07)

Primary citation

Silberstein, J.L.,Du, J.,Chan, K.W.,Frank, J.A.,Mathews, I.I.,Kim, Y.B.,You, J.,Lu, Q.,Liu, J.,Philips, E.A.,Liu, P.,Rao, E.,Fernandez, D.,Rodriguez, G.E.,Kong, X.P.,Wang, J.,Cochran, J.R.
Structural insights reveal interplay between LAG-3 homodimerization, ligand binding, and function.
Proc.Natl.Acad.Sci.USA, 121:e2310866121-e2310866121, 2024

PubMed Abstract: Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed on activated T cells and an emerging immunotherapy target. Domain 1 (D1) of LAG-3, which has been purported to directly interact with major histocompatibility complex class II (MHCII) and fibrinogen-like protein 1 (FGL1), has been the major focus for the development of therapeutic antibodies that inhibit LAG-3 receptor-ligand interactions and restore T cell function. Here, we present a high-resolution structure of glycosylated mouse LAG-3 ectodomain, identifying that cis-homodimerization, mediated through a network of hydrophobic residues within domain 2 (D2), is critically required for LAG-3 function. Additionally, we found a previously unidentified key protein-glycan interaction in the dimer interface that affects the spatial orientation of the neighboring D1 domain. Mutation of LAG-3 D2 residues reduced dimer formation, dramatically abolished LAG-3 binding to both MHCII and FGL1 ligands, and consequentially inhibited the role of LAG-3 in suppressing T cell responses. Intriguingly, we showed that antibodies directed against D1, D2, and D3 domains are all capable of blocking LAG-3 dimer formation and MHCII and FGL-1 ligand binding, suggesting a potential allosteric model of LAG-3 function tightly regulated by dimerization. Furthermore, our work reveals unique epitopes, in addition to D1, that can be targeted for immunotherapy of cancer and other human diseases.

PubMed: 38483996
DOI: 10.1073/pnas.2310866121

Experimental method

X-RAY DIFFRACTION (3.78 Å)