9v3c

Structure of C5a anaphylatoxin chemotactic receptor 2, C5aR2 bound to C5a

spinqualitylabelsall models 9v3c, resolution 3.82Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9v3c is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.82Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function C5AR2_HUMAN Receptor for the chemotactic and inflammatory peptide anaphylatoxin C5a, stimulating chemotaxis, granule enzyme release, intracellular calcium release and superoxide anion production (PubMed:11773063). Also acts as a receptor for dearginated forms of C3a, C4a and C5a anaphylatoxin peptides (ASP/C3adesArg, C4adesArg and C5adesArg, respectively) (PubMed:12540846, PubMed:15833747, PubMed:19615750). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as adenylate cyclase (PubMed:12540846). C5AR1 is coupled to G(i)/G(o) (GNAI1 or GNAO1) G alpha proteins and mediates inhibition of adenylate cyclase (PubMed:12540846). Publication Abstract from PubMed 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(-d-Arg), exhibits a robust G-protein-coupling bias at C5aR1 with attenuated beta-arrestin (betaarr) 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 betaarr-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. Molecular mechanisms of naturally encoded signaling bias at the complement anaphylatoxin receptors.,Tiwari D, Sawada K, Dalal A, Mishra S, Li XX, Dent JC, Kim K, Yadav MK, Roy N, Ganguly M, Banerjee N, Stepniewski TM, Ahn D, Yamaguchi K, Oshima HS, Hashimoto K, Fung JN, Lerskiatiphanich T, Cui CS, Lee JD, Selent J, Inoue A, Clark RJ, Chung KY, Banerjee R, Sano FK, Woodruff TM, Nureki O, Shukla AK Mol Cell. 2026 Jun 22:S1097-2765(26)00373-4. doi: 10.1016/j.molcel.2026.06.002. PMID:42330960 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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