8sr0
From Proteopedia
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== Function == | == Function == | ||
| - | [https://www.uniprot.org/uniprot/LAG3_HUMAN LAG3_HUMAN] Lymphocyte activation gene 3 protein: Inhibitory receptor on antigen activated T-cells (PubMed: | + | [https://www.uniprot.org/uniprot/LAG3_HUMAN LAG3_HUMAN] Lymphocyte activation gene 3 protein: Inhibitory receptor on antigen activated T-cells (PubMed:20421648, PubMed:7805750, PubMed:8647185). Delivers inhibitory signals upon binding to ligands, such as FGL1 (By similarity). FGL1 constitutes a major ligand of LAG3 and is responsible for LAG3 T-cell inhibitory function (By similarity). Following TCR engagement, LAG3 associates with CD3-TCR in the immunological synapse and directly inhibits T-cell activation (By similarity). May inhibit antigen-specific T-cell activation in synergy with PDCD1/PD-1, possibly by acting as a coreceptor for PDCD1/PD-1 (By similarity). Negatively regulates the proliferation, activation, effector function and homeostasis of both CD8(+) and CD4(+) T-cells (PubMed:20421648, PubMed:7805750, PubMed:8647185). Also mediates immune tolerance: constitutively expressed on a subset of regulatory T-cells (Tregs) and contributes to their suppressive function (By similarity). Also acts as a negative regulator of plasmacytoid dendritic cell (pDCs) activation (By similarity). Binds MHC class II (MHC-II); the precise role of MHC-II-binding is however unclear (PubMed:8647185).[UniProtKB:Q61790]<ref>PMID:20421648</ref> <ref>PMID:7805750</ref> <ref>PMID:8647185</ref> May function as a ligand for MHC class II (MHC-II) on antigen-presenting cells (APC), promoting APC activation/maturation and driving Th1 immune response.[UniProtKB:Q61790] |
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== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Lymphocyte activation gene 3 protein (LAG3) is an inhibitory receptor that is upregulated on exhausted T cells in tumors. LAG3 is a major target for cancer immunotherapy with many anti-LAG3 antibodies in clinical trials. However, there is no structural information on the epitopes recognized by these antibodies. We determined the single-particle cryoEM structure of a therapeutic antibody (favezelimab) bound to LAG3 to 3.5 A resolution, revealing that favezelimab targets the LAG3-binding site for MHC class II, its canonical ligand. The small size of the complex between the conventional (monovalent) Fab of favezelimab and LAG3 ( approximately 100 kDa) presented a challenge for cryoEM. Accordingly, we engineered a bivalent version of Fab favezelimab that doubled the size of the Fab-LAG3 complex and conferred a highly identifiable shape to the complex that facilitated particle selection and orientation for image processing. This study establishes bivalent Fabs as new fiducial markers for cryoEM analysis of small proteins. | Lymphocyte activation gene 3 protein (LAG3) is an inhibitory receptor that is upregulated on exhausted T cells in tumors. LAG3 is a major target for cancer immunotherapy with many anti-LAG3 antibodies in clinical trials. However, there is no structural information on the epitopes recognized by these antibodies. We determined the single-particle cryoEM structure of a therapeutic antibody (favezelimab) bound to LAG3 to 3.5 A resolution, revealing that favezelimab targets the LAG3-binding site for MHC class II, its canonical ligand. The small size of the complex between the conventional (monovalent) Fab of favezelimab and LAG3 ( approximately 100 kDa) presented a challenge for cryoEM. Accordingly, we engineered a bivalent version of Fab favezelimab that doubled the size of the Fab-LAG3 complex and conferred a highly identifiable shape to the complex that facilitated particle selection and orientation for image processing. This study establishes bivalent Fabs as new fiducial markers for cryoEM analysis of small proteins. | ||
| - | CryoEM structure of a therapeutic antibody (favezelimab) bound to human LAG3 determined using a bivalent Fab as fiducial marker.,Mishra AK, Shahid S, Karade SS, Agnihotri P, Kolesnikov A, Hasan SS, Mariuzza RA Structure. 2023 | + | CryoEM structure of a therapeutic antibody (favezelimab) bound to human LAG3 determined using a bivalent Fab as fiducial marker.,Mishra AK, Shahid S, Karade SS, Agnihotri P, Kolesnikov A, Hasan SS, Mariuzza RA Structure. 2023 Oct 5;31(10):1149-1157.e3. doi: 10.1016/j.str.2023.07.013. Epub , 2023 Aug 23. PMID:37619561<ref>PMID:37619561</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
CryoEM structure of a therapeutic antibody (favezelimab) bound to human LAG3 local refined
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