Human LAG-3 homodimer (with domains D1, D2, D3 and D4) binding to 2 separate HLA-II (MHC-II) molecules on the floor of an antigen-presenting cell (APC), imposing a definite 38° offset angle. This determine has been modified from the unique determine 1c of Petersen et al to help visualization. Credit score: Monash College
Australian-led analysis is unlocking new methods for immunotherapy to raised goal most cancers. Most cancers immunotherapy has revolutionized therapy for sufferers, whereby the physique’s personal immune system is harnessed to destroy most cancers cells.
Usually, a number of molecules restrain the flexibility of T cells to focus on most cancers cells and growing approaches to restrict this restraining impact can result in improved effectiveness of most cancers immunotherapy.
Analysis printed in Science Immunology has decided the construction of how an inhibitory molecule, LAG3, interacts with its important ligand and offers a brand new focused method to bettering the effectiveness of immunotherapy for sure types of most cancers.
The publication is the primary to point out the crystal construction of a human LAG-3/HLA-II advanced and offers a greater basis for growth of blocking LAG-3 therapeutics.
Led by Professor Jamie Rossjohn at Monash College’s Biomedicine Discovery Institute (BDI), in Melbourne, Australia, in collaboration with Immutep, this analysis resolves how the human LAG-3 receptor binds to HLA II molecules.
First creator Dr. Jan Petersen mentioned, “The way in which the PD-1 and CTLA-4 immune checkpoint molecules bind to their respective ligands has been resolved for a few years.
“Nevertheless, the decision of the interface between one other essential checkpoint molecule, LAG-3, and its important ligands, HLA-II molecules, has remained elusive.
“Solved using data collected at the Australian Synchrotron, a structure of a LAG-3/HLA-II complex provides a structural foundation to harness rationally for future development of antibodies and small molecule therapeutics designed to block LAG-3 activity.”
Dr. Frédéric Triebel, Immutep’s CSO, added, “These findings add to the strong foundation of our work with Professor Rossjohn and his team to develop a deeper understanding of the structure and function of the LAG-3 immune control mechanism, particularly as it relates to our anti-LAG-3 small molecule program.”
Extra info:
Jan Petersen et al, Crystal construction of the human LAG-3–HLA-DR1–peptide advanced, Science Immunology (2024). DOI: 10.1126/sciimmunol.ads5122. www.science.org/doi/10.1126/sciimmunol.ads5122
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Molecular insights unlock a focused method to most cancers immunotherapy (2024, December 13)
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