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Structural visualization of small molecule recognition by CXCR3 uncovers dual-agonism in the CXCR3-CXCR7 system

Author

Listed:
  • Shirsha Saha

    (Indian Institute of Technology Kanpur)

  • Fumiya K. Sano

    (The University of Tokyo)

  • Saloni Sharma

    (Indian Institute of Technology Kanpur)

  • Manisankar Ganguly

    (Indian Institute of Technology Kanpur)

  • Annu Dalal

    (Indian Institute of Technology Kanpur)

  • Sudha Mishra

    (Indian Institute of Technology Kanpur)

  • Divyanshu Tiwari

    (Indian Institute of Technology Kanpur)

  • Hiroaki Akasaka

    (The University of Tokyo)

  • Takaaki A. Kobayashi

    (The University of Tokyo)

  • Nabarun Roy

    (Indian Institute of Technology Kanpur)

  • Nashrah Zaidi

    (Indian Institute of Technology Kanpur)

  • Yuzuru Itoh

    (The University of Tokyo)

  • Rob Leurs

    (VU University Amsterdam)

  • Ramanuj Banerjee

    (Indian Institute of Technology Kanpur)

  • Wataru Shihoya

    (The University of Tokyo)

  • Osamu Nureki

    (The University of Tokyo)

  • Arun K. Shukla

    (Indian Institute of Technology Kanpur)

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.

Suggested Citation

  • Shirsha Saha & Fumiya K. Sano & Saloni Sharma & Manisankar Ganguly & Annu Dalal & Sudha Mishra & Divyanshu Tiwari & Hiroaki Akasaka & Takaaki A. Kobayashi & Nabarun Roy & Nashrah Zaidi & Yuzuru Itoh &, 2025. "Structural visualization of small molecule recognition by CXCR3 uncovers dual-agonism in the CXCR3-CXCR7 system," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58264-w
    DOI: 10.1038/s41467-025-58264-w
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    References listed on IDEAS

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    1. Dylan Scott Eiger & Noelia Boldizsar & Christopher Cole Honeycutt & Julia Gardner & Stephen Kirchner & Chloe Hicks & Issac Choi & Uyen Pham & Kevin Zheng & Anmol Warman & Jeffrey S. Smith & Jennifer Y, 2022. "Location bias contributes to functionally selective responses of biased CXCR3 agonists," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Parishmita Sarma & Carlo Marion C. Carino & Deeksha Seetharama & Shubhi Pandey & Hemlata Dwivedi-Agnihotri & Xue Rui & Yubo Cao & Kouki Kawakami & Poonam Kumari & Yu-Chih Chen & Kathryn E. Luker & Pre, 2023. "Molecular insights into intrinsic transducer-coupling bias in the CXCR4-CXCR7 system," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
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