Molecular basis of diverse ligand recognition and species-specific pharmacology at the complement anaphylatoxin receptor C3aR
The complement anaphylatoxin receptor, C3aR, is a prototypical G protein-coupled receptor (GPCR) that plays multi-faceted roles in immune regulation, pro-inflammatory responses, neuroimmune modulation, and host defense mechanisms against pathogens. Recent structural coverage has provided important insights into C3aR activation and signaling, however, confounding observations in the literature related to ligand efficacy and functional responses present a major challenge for drug discovery efforts. Here, we systematically and comprehensively profile a broad set of natural and synthetic ligands at C3aR, and demonstrate functional specialization in terms of species-specific pharmacology, receptor activation, and signaling-bias. Taking a lead from this, we determine seven cryo-EM structures of C3aR, and employ structure-guided site-directed mutagenesis studies to decode a convergent molecular mechanism that orchestrates the recognition and efficacy of diverse agonists. This study elucidates key molecular insights into C3aR activation and signaling with direct implications for therapeutic design. The complement anaphylatoxin receptor, C3aR is a potential drug target in various inflammatory disorders. Here, authors present insights into its activation, signaling, and pharmacology that is likely to facilitate therapeutic design going forward.
Authors
- Cedric S. Cui (ORCID: https://orcid.org/0000-0002-0534-027X)
- Jenny N. Fung (ORCID: https://orcid.org/0000-0002-7840-8490)
- Parishmita Sarma (ORCID: https://orcid.org/0000-0001-5519-7160)
- Osamu Nureki (ORCID: https://orcid.org/0000-0003-1813-7008)
- Manisankar Ganguly
- Cornelius Gati (ORCID: https://orcid.org/0000-0003-3693-7009)
- Richard J. Clark (ORCID: https://orcid.org/0000-0002-6807-5426)
- K. Sawada (ORCID: https://orcid.org/0000-0002-7582-2354)
- Xaria X. Li (ORCID: https://orcid.org/0000-0001-5924-2977)
- Ramanuj Banerjee (ORCID: https://orcid.org/0000-0002-7751-2317)
- Nilanjana Banerjee (ORCID: https://orcid.org/0000-0001-8022-8598)
- Trent M. Woodruff (ORCID: https://orcid.org/0000-0003-1382-911X)
- Htet A. Khant
- Fumiya K. Sano (ORCID: https://orcid.org/0000-0002-8965-788X)
- Nabarun Roy
- Ravi Yadav (ORCID: https://orcid.org/0000-0003-2879-0465)
- Arun K. Shukla (ORCID: https://orcid.org/0000-0003-2910-8288)
- John D. Lee (ORCID: https://orcid.org/0000-0002-9976-7396)
- Jianina Marallag (ORCID: https://orcid.org/0000-0002-3179-7089)
- Houming Zhu
- Divyanshu Tiwari
- Annu Dalal
- Sudha Mishra
- Calvin A. Dsouza
- Manish K. Yadav
- Ganita Rawat
Institutions
- University of Southern California (US)
- The University of Queensland (AU)
- Convergent Science (United States) (US)
- The University of Tokyo (JP)
- Indian Institute of Technology Kanpur (IN)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-08-25
- DOI
- https://doi.org/10.1038/s41467-026-76518-z
- Primary Topic
- Complement system in diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Arthritis National Research Foundation
- University of Southern California
- Japan Agency for Medical Research and Development
- Indian Institute of Technology Kanpur
- Department of Science and Technology, Ministry of Science and Technology, India
- Indian Council of Medical Research
- National Institutes of Health
- Medical Research Council
- National Health and Medical Research Council
- Japan Society for the Promotion of Science
- Science and Engineering Research Board