Multiple intramolecular triggers converge to preferential G protein coupling in the CB2R
G protein-coupled receptors (GPCRs) are important therapeutic drug targets for a wide range of diseases. Upon activation, GPCRs can initiate several signaling pathways, each with unique therapeutic implications. Therefore, understanding how drugs selectively engage specific signaling pathways becomes paramount. However, achieving this selectivity remains highly challenging. To unravel the underlying multifaceted mechanisms, we integrate systematic mutagenesis of the CB<sub>2</sub>R, comprehensive profiling of G<sub>αi2</sub> and β-arrestin1 engagements and computer simulations to track the effects of mutations on receptor dynamics. Our research reveals multiple triggers within a complex allosteric communication network (ACN) that converge to preferential CB<sub>2</sub>R coupling by modulating evolutionarily conserved motifs. Utilizing network path analysis, we find that potent triggers are typically highly connected nodes and are located near regions of high information transmission within the ACN. Our insights highlight the complexity of GPCR signaling and provide a framework for the rational design of drug candidates tailored to evoke specific functional responses, ultimately enhancing the precision and efficacy of therapeutic interventions.
Authors
- Dmitry B. Veprintsev (ORCID: https://orcid.org/0000-0002-3583-5409)
- Adrián Morales-Pastor
- Miguel Dieguez-Eceolaza (ORCID: https://orcid.org/0009-0008-9169-6416)
- Tilman Flock
- Eline J. Koers (ORCID: https://orcid.org/0000-0002-5352-9069)
- Bianca Plouffe (ORCID: https://orcid.org/0000-0002-8321-0796)
- Wolfgang Guba (ORCID: https://orcid.org/0000-0002-3285-5957)
- David A. Sykes (ORCID: https://orcid.org/0000-0002-6606-888X)
- Christian Le Gouill (ORCID: https://orcid.org/0000-0002-6455-1800)
- Uwe Grether (ORCID: https://orcid.org/0000-0002-3164-9270)
- Tamara Miljuš (ORCID: https://orcid.org/0000-0003-0462-7866)
- Tomasz Maciej Stępniewski (ORCID: https://orcid.org/0000-0002-6828-9192)
- Franziska M. Heydenreich (ORCID: https://orcid.org/0000-0002-8049-4383)
- Jana Selent (ORCID: https://orcid.org/0000-0002-1844-4449)
- Jean Duchaine
- Arne C. Rufer (ORCID: https://orcid.org/0000-0001-5092-7478)
- Colin Nicholson
- Michel Bouvier (ORCID: https://orcid.org/0000-0003-1128-0100)
- Vicente Ledesma-Martin
Institutions
- Roche (Switzerland) (CH)
- Queen's University Belfast (GB)
- University of Nottingham (GB)
- Philipps University of Marburg (DE)
- Universitat Pompeu Fabra (ES)
- Paul Scherrer Institute (CH)
- ETH Zurich (CH)
- Institute for Research in Immunology and Cancer (CA)
- Biotech Park (IN)
- Université de Montréal (CA)
- University of Birmingham (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-06-11
- DOI
- https://doi.org/10.1038/s41467-025-60003-0
- Citations
- 6
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 12.04
Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- HORIZON EUROPE Framework Programme
- Medical Research Council
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación