Molecular basis of CXC chemokine receptor 3 ligand multispecificity
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.
Authors
- Matthieu Masureel (ORCID: https://orcid.org/0000-0002-4059-6166)
- Sigrid Noreng (ORCID: https://orcid.org/0000-0001-5767-1399)
- Laëtitia Comps‐Agrar (ORCID: https://orcid.org/0000-0002-5260-6536)
- Shannon T. Smith (ORCID: https://orcid.org/0000-0002-1225-8928)
- Caleigh M. Azumaya (ORCID: https://orcid.org/0000-0002-3484-9921)
- Tricia Zhou (ORCID: https://orcid.org/0009-0005-1080-3143)
- Hoangdung Ho (ORCID: https://orcid.org/0000-0002-1964-0660)
- Alexandre Bouyssou (ORCID: https://orcid.org/0009-0004-9294-2229)
- Eric Janezic
- Peter Liu (ORCID: https://orcid.org/0000-0002-8703-6967)
- Yang Ying (ORCID: https://orcid.org/0000-0002-0112-3016)
- Christine Tam
- Dawei Sun (ORCID: https://orcid.org/0009-0005-3379-5369)
- Prajakta Joshi
- Shu Ti
Institutions
- Genomic Health (United States) (US)
- Sunesis (United States) (US)
Publication Details
- Journal
- Science Advances
- Published
- 2026-04-17
- DOI
- https://doi.org/10.1126/sciadv.adz3767
- Primary Topic
- Chemokine receptors and signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00