7tz2

Structure of human Fibrinogen-like protein 1Structure of human Fibrinogen-like protein 1

Structural highlights

7tz2 is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[FGL1_HUMAN] Immune suppressive molecule that inhibits antigen-specific T-cell activation by acting as a major ligand of LAG3 (PubMed:30580966). Responsible for LAG3 T-cell inhibitory function (PubMed:30580966). Binds LAG3 independently from MHC class II (MHC-II) (PubMed:30580966). Secreted by, and promotes growth of, hepatocytes (PubMed:11470158, PubMed:19880967).^[1] ^[2] ^[3]

Publication Abstract from PubMed

The immune checkpoint receptor lymphocyte activation gene 3 protein (LAG3) inhibits T cell function upon binding to major histocompatibility complex class II (MHC class II) or fibrinogen-like protein 1 (FGL1). Despite the emergence of LAG3 as a target for next-generation immunotherapies, we have little information describing the molecular structure of the LAG3 protein or how it engages cellular ligands. Here we determined the structures of human and murine LAG3 ectodomains, revealing a dimeric assembly mediated by Ig domain 2. Epitope mapping indicates that a potent LAG3 antagonist antibody blocks interactions with MHC class II and FGL1 by binding to a flexible 'loop 2' region in LAG3 domain 1. We also defined the LAG3-FGL1 interface by mapping mutations onto structures of LAG3 and FGL1 and established that FGL1 cross-linking induces the formation of higher-order LAG3 oligomers. These insights can guide LAG3-based drug development and implicate ligand-mediated LAG3 clustering as a mechanism for disrupting T cell activation.

LAG3 ectodomain structure reveals functional interfaces for ligand and antibody recognition.,Ming Q, Celias DP, Wu C, Cole AR, Singh S, Mason C, Dong S, Tran TH, Amarasinghe GK, Ruffell B, Luca VC Nat Immunol. 2022 Jun 27. pii: 10.1038/s41590-022-01238-7. doi:, 10.1038/s41590-022-01238-7. PMID:35761082^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hara H, Yoshimura H, Uchida S, Toyoda Y, Aoki M, Sakai Y, Morimoto S, Shiokawa K. Molecular cloning and functional expression analysis of a cDNA for human hepassocin, a liver-specific protein with hepatocyte mitogenic activity. Biochim Biophys Acta. 2001 Jul 30;1520(1):45-53. PMID:11470158
↑ Li CY, Cao CZ, Xu WX, Cao MM, Yang F, Dong L, Yu M, Zhan YQ, Gao YB, Li W, Wang ZD, Ge CH, Wang QM, Peng RY, Yang XM. Recombinant human hepassocin stimulates proliferation of hepatocytes in vivo and improves survival in rats with fulminant hepatic failure. Gut. 2010 Jun;59(6):817-26. doi: 10.1136/gut.2008.171124. Epub 2009 Nov 1. PMID:19880967 doi:http://dx.doi.org/10.1136/gut.2008.171124
↑ Wang J, Sanmamed MF, Datar I, Su TT, Ji L, Sun J, Chen L, Chen Y, Zhu G, Yin W, Zheng L, Zhou T, Badri T, Yao S, Zhu S, Boto A, Sznol M, Melero I, Vignali DAA, Schalper K, Chen L. Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3. Cell. 2019 Jan 10;176(1-2):334-347.e12. doi: 10.1016/j.cell.2018.11.010. Epub, 2018 Dec 20. PMID:30580966 doi:http://dx.doi.org/10.1016/j.cell.2018.11.010
↑ Ming Q, Celias DP, Wu C, Cole AR, Singh S, Mason C, Dong S, Tran TH, Amarasinghe GK, Ruffell B, Luca VC. LAG3 ectodomain structure reveals functional interfaces for ligand and antibody recognition. Nat Immunol. 2022 Jun 27. pii: 10.1038/s41590-022-01238-7. doi:, 10.1038/s41590-022-01238-7. PMID:35761082 doi:http://dx.doi.org/10.1038/s41590-022-01238-7

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OCA

[1] Hara H, Yoshimura H, Uchida S, Toyoda Y, Aoki M, Sakai Y, Morimoto S, Shiokawa K. Molecular cloning and functional expression analysis of a cDNA for human hepassocin, a liver-specific protein with hepatocyte mitogenic activity. Biochim Biophys Acta. 2001 Jul 30;1520(1):45-53. PMID:11470158

[2] Li CY, Cao CZ, Xu WX, Cao MM, Yang F, Dong L, Yu M, Zhan YQ, Gao YB, Li W, Wang ZD, Ge CH, Wang QM, Peng RY, Yang XM. Recombinant human hepassocin stimulates proliferation of hepatocytes in vivo and improves survival in rats with fulminant hepatic failure. Gut. 2010 Jun;59(6):817-26. doi: 10.1136/gut.2008.171124. Epub 2009 Nov 1. PMID:19880967 doi:http://dx.doi.org/10.1136/gut.2008.171124

[3] Wang J, Sanmamed MF, Datar I, Su TT, Ji L, Sun J, Chen L, Chen Y, Zhu G, Yin W, Zheng L, Zhou T, Badri T, Yao S, Zhu S, Boto A, Sznol M, Melero I, Vignali DAA, Schalper K, Chen L. Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3. Cell. 2019 Jan 10;176(1-2):334-347.e12. doi: 10.1016/j.cell.2018.11.010. Epub, 2018 Dec 20. PMID:30580966 doi:http://dx.doi.org/10.1016/j.cell.2018.11.010

[4] Ming Q, Celias DP, Wu C, Cole AR, Singh S, Mason C, Dong S, Tran TH, Amarasinghe GK, Ruffell B, Luca VC. LAG3 ectodomain structure reveals functional interfaces for ligand and antibody recognition. Nat Immunol. 2022 Jun 27. pii: 10.1038/s41590-022-01238-7. doi:, 10.1038/s41590-022-01238-7. PMID:35761082 doi:http://dx.doi.org/10.1038/s41590-022-01238-7

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