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-Structure paper
| Title | Molecular basis of CXC chemokine receptor 3 ligand multispecificity. |
|---|---|
| Journal, issue, pages | Sci Adv, Vol. 12, Issue 16, Page eadz3767, Year 2026 |
| Publish date | Apr 17, 2026 |
Authors | Alexandre Bouyssou / Dawei Sun / Tricia Zhou / Shannon Smith / Hoangdung Ho / Matthew Johnson / Caleigh Azumaya / Sigrid Noreng / Peter Liu / Shu Ti / Prajakta Joshi / Christine Tam / Ying Yang / Eric Janezic / Laëtitia Comps-Agrar / Matthieu Masureel / ![]() |
| PubMed Abstract | C-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 ...C-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 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. |
External links | Sci Adv / PubMed:41996512 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.95 - 3.5 Å |
| Structure data | ![]() EMDB-71075: Consensus map of CXCL9-CXCR3-Gi-scFv16 ![]() EMDB-71077: Focused map of CXCL9-CXCR3 ![]() EMDB-71078: Focused map of Gi-scFv16 (components of CXCL9-CXCR3-Gi-scFv16) EMDB-71079, PDB-9p0k: EMDB-71080, PDB-9p0l: EMDB-71081, PDB-9p0m: ![]() EMDB-71082: consensus map of CXCL11-CXCR3-Gi-scFv16 ![]() EMDB-71083: Focused map of CXCL11-CXCR3 (components of CXCL11-CXCR3-Gi-scFv16) ![]() EMDB-71084: Focused map of Gi_scFv16 (components of CXCL11-CXCR3-Gi-scFv16) ![]() EMDB-71085: consensus map of CXCL10-CXCR3-Gi-scFv16 ![]() EMDB-71086: Focused map of CXCL10-CXCR3 (components of CXCL10-CXCR3-Gi-scFv16) ![]() EMDB-71087: Focused map of Gi-scFv16 (components of CXCL10-CXCR3-Gi-scFv16) |
| Source |
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Keywords | MEMBRANE PROTEIN / GPCR / chemokine receptor / IMMUNE SYSTEM |
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