8Y0N

Structure of CXCR3 in complex with VUF11418 and Go (Full map)

This is a non-PDB format compatible entry.

Summary for 8Y0N

• Entry DOI: 10.2210/pdb8y0n/pdb
• EMDB information: 38809
• Descriptor: Guanine nucleotide-binding protein G(o) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, arrestin, signaling protein-immune system complex, signaling protein-immune complex, signaling protein/immune
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 146956.78

Authors

Sano, F.K.,Saha, S.,Sharma, S.,Ganguly, M.,Shihoya, W.,Nureki, O.,Shukla, A.K.,Banerjee, R. (deposition date: 2024-01-22, release date: 2025-02-26, Last modification date: 2025-04-09)

Primary citation

Saha, S.,Sano, F.K.,Sharma, S.,Ganguly, M.,Dalal, A.,Mishra, S.,Tiwari, D.,Akasaka, H.,Kobayashi, T.A.,Roy, N.,Zaidi, N.,Itoh, Y.,Leurs, R.,Banerjee, R.,Shihoya, W.,Nureki, O.,Shukla, A.K.
Structural visualization of small molecule recognition by CXCR3 uncovers dual-agonism in the CXCR3-CXCR7 system.
Nat Commun, 16:3047-3047, 2025

PubMed Abstract: Chemokine receptors are critically involved in multiple physiological and pathophysiological processes related to immune response mechanisms. Most chemokine receptors are prototypical GPCRs although some also exhibit naturally-encoded signaling-bias toward β-arrestins (βarrs). C-X-C type chemokine receptors, namely CXCR3 and CXCR7, constitute a pair wherein the former is a prototypical GPCR while the latter exhibits selective coupling to βarrs despite sharing a common natural agonist: CXCL11. Moreover, CXCR3 and CXCR7 also recognize small molecule agonists suggesting a modular orthosteric ligand binding pocket. Here, we determine cryo-EM structures of CXCR3 in an Apo-state and in complex with small molecule agonists biased toward G-proteins or βarrs. These structural snapshots uncover an allosteric network bridging the ligand-binding pocket to intracellular side, driving the transducer-coupling bias at this receptor. Furthermore, structural topology of the orthosteric binding pocket also allows us to discover and validate that selected small molecule agonists of CXCR3 display robust agonism at CXCR7. Collectively, our study offers molecular insights into signaling-bias and dual agonism in the CXCR3-CXCR7 system with therapeutic implications.

PubMed: 40155369
DOI: 10.1038/s41467-025-58264-w

Experimental method

ELECTRON MICROSCOPY (3.07 Å)