Structural visualization of small molecule recognition by CXCR3 uncovers dual-agonism in the CXCR3-CXCR7 system
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 ch...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-03-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58264-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850063744625803264 |
|---|---|
| author | 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 Rob Leurs Ramanuj Banerjee Wataru Shihoya Osamu Nureki Arun K. Shukla |
| author_facet | 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 Rob Leurs Ramanuj Banerjee Wataru Shihoya Osamu Nureki Arun K. Shukla |
| author_sort | Shirsha Saha |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9d5578f9da7a45c3bfb153062c28f681 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-9d5578f9da7a45c3bfb153062c28f6812025-08-20T02:49:30ZengNature PortfolioNature Communications2041-17232025-03-0116111810.1038/s41467-025-58264-wStructural visualization of small molecule recognition by CXCR3 uncovers dual-agonism in the CXCR3-CXCR7 systemShirsha Saha0Fumiya K. Sano1Saloni Sharma2Manisankar Ganguly3Annu Dalal4Sudha Mishra5Divyanshu Tiwari6Hiroaki Akasaka7Takaaki A. Kobayashi8Nabarun Roy9Nashrah Zaidi10Yuzuru Itoh11Rob Leurs12Ramanuj Banerjee13Wataru Shihoya14Osamu Nureki15Arun K. Shukla16Department of Biological Sciences and Bioengineering, Indian Institute of Technology KanpurDepartment of Biological Sciences, Graduate School of Science, The University of TokyoDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology KanpurDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology KanpurDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology KanpurDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology KanpurDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology KanpurDepartment of Biological Sciences, Graduate School of Science, The University of TokyoDepartment of Biological Sciences, Graduate School of Science, The University of TokyoDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology KanpurDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology KanpurDepartment of Biological Sciences, Graduate School of Science, The University of TokyoAmsterdam Institute for Molecules, Medicines, and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, VU University AmsterdamDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology KanpurDepartment of Biological Sciences, Graduate School of Science, The University of TokyoDepartment of Biological Sciences, Graduate School of Science, The University of TokyoDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology KanpurAbstract 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.https://doi.org/10.1038/s41467-025-58264-w |
| spellingShingle | 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 Rob Leurs Ramanuj Banerjee Wataru Shihoya Osamu Nureki Arun K. Shukla Structural visualization of small molecule recognition by CXCR3 uncovers dual-agonism in the CXCR3-CXCR7 system Nature Communications |
| title | Structural visualization of small molecule recognition by CXCR3 uncovers dual-agonism in the CXCR3-CXCR7 system |
| title_full | Structural visualization of small molecule recognition by CXCR3 uncovers dual-agonism in the CXCR3-CXCR7 system |
| title_fullStr | Structural visualization of small molecule recognition by CXCR3 uncovers dual-agonism in the CXCR3-CXCR7 system |
| title_full_unstemmed | Structural visualization of small molecule recognition by CXCR3 uncovers dual-agonism in the CXCR3-CXCR7 system |
| title_short | Structural visualization of small molecule recognition by CXCR3 uncovers dual-agonism in the CXCR3-CXCR7 system |
| title_sort | structural visualization of small molecule recognition by cxcr3 uncovers dual agonism in the cxcr3 cxcr7 system |
| url | https://doi.org/10.1038/s41467-025-58264-w |
| work_keys_str_mv | AT shirshasaha structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system AT fumiyaksano structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system AT salonisharma structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system AT manisankarganguly structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system AT annudalal structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system AT sudhamishra structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system AT divyanshutiwari structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system AT hiroakiakasaka structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system AT takaakiakobayashi structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system AT nabarunroy structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system AT nashrahzaidi structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system AT yuzuruitoh structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system AT robleurs structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system AT ramanujbanerjee structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system AT watarushihoya structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system AT osamunureki structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system AT arunkshukla structuralvisualizationofsmallmoleculerecognitionbycxcr3uncoversdualagonisminthecxcr3cxcr7system |