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| Title | Molecular mechanisms of naturally encoded signaling bias at the complement anaphylatoxin receptors. |
|---|---|
| Journal, issue, pages | Mol Cell, Vol. 86, Issue 13, Page 2586-2604.e14, Year 2026 |
| Publish date | Jul 2, 2026 |
 Authors | Divyanshu Tiwari / Kazuhiro Sawada / Annu Dalal / Sudha Mishra / Xaria X Li / Joshua C Dent / Kiae Kim / Manish K Yadav / Nabarun Roy / Manisankar Ganguly / Nilanjana Banerjee / Tomasz Maciej Stepniewski / Donghoon Ahn / Kohei Yamaguchi / Hidetaka S Oshima / Kana Hashimoto / Jenny N Fung / Titaya Lerskiatiphanich / Cedric S Cui / John D Lee / Jana Selent / Asuka Inoue / Richard J Clark / Ka Young Chung / Ramanuj Banerjee / Fumiya K Sano / Trent M Woodruff / Osamu Nureki / Arun K Shukla /      |
| PubMed Abstract | The conceptual framework of biased agonism has greatly impacted our understanding of G-protein-coupled receptor (GPCR) signaling, regulatory paradigms, and drug discovery efforts. Here, we present ...The conceptual framework of biased agonism has greatly impacted our understanding of G-protein-coupled receptor (GPCR) signaling, regulatory paradigms, and drug discovery efforts. Here, we present fundamental molecular and structural insights into intrinsic bias encoded at the human and mouse complement anaphylatoxin C5a receptors, namely C5aR1 and C5aR2. We discover that a naturally occurring version of C5a, i.e., C5a, exhibits a robust G-protein-coupling bias at C5aR1 with attenuated β-arrestin (βarr) recruitment, which originates from a distinct conformation of TM7 and helix 8 in the receptor, leading to inefficient GRK recruitment and phosphorylation. We also determine a series of cryo-electron microscopy (cryo-EM) structures of C5aR2, a naturally encoded βarr-biased receptor, which uncover key differences in anaphylatoxin recognition by C5aR2 relative to C5aR1. These structural snapshots also uncover a shallower cytoplasmic pocket in C5aR2 with a hydrophobic interior, which is likely incompatible with efficient G-protein coupling, leading to intrinsic bias. Our findings illuminate the molecular basis of naturally encoded signaling bias at GPCRs, with direct implications for therapeutic design. |
 External links | Mol Cell / PubMed:42330960 |
| Methods | EM (single particle) |
| Resolution | 2.97 - 3.82 Å |
| Structure data | EMDB-64749, PDB-9v35: EMDB-64751, PDB-9v38: EMDB-64752, PDB-9v3c: EMDB-64761, PDB-9v3y: EMDB-64777, PDB-9v4d: EMDB-65890, PDB-9wdi: EMDB-80132, PDB-25if: |
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 Keywords | SIGNALING PROTEIN / G protein coupled receptor / G protein / Membrane protein / Immunite system |
homo sapiens (human)
mus musculus (house mouse)