9p0l
Composite map of CXCL10-CXCR3-Gi-scFv16
Structural highlights
FunctionU6GSR1_EIMAC CXCR3_HUMAN Receptor for the C-X-C chemokine CXCL9, CXCL10 and CXCL11 and mediates the proliferation, survival and angiogenic activity of human mesangial cells (HMC) through a heterotrimeric G-protein signaling pathway (PubMed:12782716). Binds to CCL21. Probably promotes cell chemotaxis response. Upon activation by PF4, induces activated T-lymphocytes migration mediated via downstream Ras/extracellular signal-regulated kinase (ERK) signaling.[1] [2] [3] Receptor for the C-X-C chemokine CXCL4 and also mediates the inhibitory activities of CXCL9, CXCL10 and CXCL11 on the proliferation, survival and angiogenic activity of human microvascular endothelial cells (HMVEC) through a cAMP-mediated signaling pathway (PubMed:12782716). Does not promote cell chemotaxis respons. Interaction with CXCL4 or CXCL10 leads to activation of the p38MAPK pathway and contributes to inhibition of angiogenesis. Overexpression in renal cancer cells down-regulates expression of the anti-apoptotic protein HMOX1 and promotes apoptosis.[4] Mediates the activity of CXCL11. Publication Abstract from PubMedC-X-C motif chemokine receptor 3 (CXCR3) is essential for immune cell functions and pivotal in T helper 1 cell infiltration in autoimmune and chronic inflammatory diseases and in tumor proliferation and metastasis, but the mechanisms by which the endogenous ligands CXCL9, CXCL10, and CXCL11 differentially recognize and activate CXCR3 are not fully understood. Here, we present cryo-electron microscopy structures of all three chemokine-CXCR3-G(i) complexes, complemented by cell binding studies and functional mutagenesis data. We systematically compare the pharmacological and interaction profiles of CXCL9, CXCL10, and CXCL11 to rationalize their varying efficacies and potencies and to reveal the critical role of the membrane-distal CXCR3 N terminus in ligand binding and signaling. Using chimeric chemokines and molecular dynamics, we reveal the signaling plasticity of chemokine ligands and signaling determinants. Together, these insights enable us to propose a multimodal binding and activation framework that explains CXCR3 chemokine ligand multispecificity and signaling versatility and offer tools to interrogate and modulate CXCR3 biology. Molecular basis of CXC chemokine receptor 3 ligand multispecificity.,Bouyssou A, Sun D, Zhou T, Smith S, Ho H, Johnson M, Azumaya C, Noreng S, Liu P, Ti S, Joshi P, Tam C, Yang Y, Janezic E, Comps-Agrar L, Masureel M Sci Adv. 2026 Apr 17;12(16):eadz3767. doi: 10.1126/sciadv.adz3767. Epub 2026 Apr , 17. PMID:41996512[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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