New Insights into the Molecular Structure of LAG-3

Lymphocyte activation gene-3 (LAG-3) has emerged as one of the most promising and potential targets in cancer therapy. Creative Biolabs shares new advances in structural studies of the LAG-3 molecule, providing researchers with new insights for future basic and applied studies.

Why Delve into the LAG-3 Structure?

A major function of LAG-3 is to negatively regulate major histocompatibility complex class II (MHCII)-mediated T cell activation. In addition to MHCII, multiple other ligands for LAG-3 have been identified, namely fibrinogen-like protein 1 (FGL1), LSECtin, galectin 3, and α-synuclein. Although LAG3 is expressed in T cells in a TCR signaling-dependent manner, it is also present and active on immune cells lacking TCR expression.

Thus, this suggests that LAG-3 biology is relatively complex and that LAG-3 may have multiple functions.

Therefore, an in-depth study of the molecular structure, epitopes and functions of LAG-3 will

• Enhance our understanding of the LAG-3 signaling axis.
• Clarify how LAG-3 regulates changes in T cell activity.
• Guide the development of the most effective immunotherapies targeting LAG-3.

New Structure of LAG-3

Researchers co-crystallized the LAG-3 D1-D4 domains with a single-chain variable fragment (scFv) of an antagonist to characterize the structure of the LAG-3 extracellular domain.

• It was found that LAG-3 is formed as a homodimer through the D2 structural domain, with the remaining structural domains forming an elongated and curved arrangement. The dimer interface in D2 is at an angle, so that the D1 structural domain deviates from the central axis of the dimer and forms a V-shaped aperture.
• The dimerization interfaces in human and mouse LAG-3 structures share a broadly conserved set of residues, but the angles of D1D2 dimer formation are extremely different. This may result in different relative positions of the MHCII and FGL1 binding sites. This conformational difference between human and mouse LAG-3 may reflect two distinct functional states of LAG-3.
• In addition to resolving structural information on the extracellular structural domain of LAG-3, key interfacial residues in the LAG-3 D1 loop 2 were identified and it was demonstrated that LAG-3 binds MHCII and FGL1 via different molecular surfaces.

Clinical Development of LAG-3

Many biopharmaceutical companies are currently investing in and developing LAG-3 programs, and there are currently at least one hundred clinical trials related to LAG-3 in clinical trials. To date, at least 20 drugs have been developed that target LAG-3. These include anti-LAG-3 blocking antibodies, as well as antagonistic bispecific antibodies.

Structural studies of LAG-3 have not only provided insights into the biology of LAG-3, but have also laid the foundation for the evaluation of agonist and antagonist antibodies against LAG-3 and the rational development of small-molecule inhibitors targeting LAG3-ligand interactions.

Creative Biolabs learns and continues to explore a number of important recent studies, which assist us in providing LAG-3 related services to our customers.

All listed customized services & products are for research use only, not intended for pharmaceutical, diagnostic, therapeutic, or any in vivo human use.