7y66 | pdb_00007y66

Cryo-EM structure of BM213-bound C5aR1 in complex with Gi protein

spinqualitylabelsall models 7y66, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7y66 is a 6 chain structure with sequence from Homo sapiens, Mus musculus and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.9Å Ligands: ACE, DAL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The complement system plays an important role in the innate immune response to invading pathogens. The complement fragment C5a is one of its important effector components and exerts diverse physiological functions through activation of the C5a receptor 1 (C5aR1) and associated downstream G protein and beta-arrestin signaling pathways. Dysfunction of the C5a-C5aR1 axis is linked to numerous inflammatory and immune-mediated diseases, but the structural basis for activation and biased signaling of C5aR1 remains elusive. Here, we present cryo-electron microscopy structures of the activated wild-type C5aR1-G(i) protein complex bound to each of the following: C5a, the hexapeptidic agonist C5a(pep), and the G protein-biased agonist BM213. The structures reveal the landscape of the C5a-C5aR1 interaction as well as a common motif for the recognition of diverse orthosteric ligands. Moreover, combined with mutagenesis studies and cell-based pharmacological assays, we deciphered a framework for biased signaling using different peptide analogs and provided insight into the activation mechanism of C5aR1 by solving the structure of C5aR1(I116A) mutant-G(i) signaling activation complex induced by C089, which exerts antagonism on wild-type C5aR1. In addition, unusual conformational changes in the intracellular end of transmembrane domain 7 and helix 8 upon agonist binding suggest a differential signal transduction process. Collectively, our study provides mechanistic understanding into the ligand recognition, biased signaling modulation, activation, and G(i) protein coupling of C5aR1, which may facilitate the future design of therapeutic agents. Mechanism of activation and biased signaling in complement receptor C5aR1.,Feng Y, Zhao C, Deng Y, Wang H, Ma L, Liu S, Tian X, Wang B, Bin Y, Chen P, Yan W, Fu P, Shao Z Cell Res. 2023 Apr;33(4):312-324. doi: 10.1038/s41422-023-00779-2. Epub 2023 Feb , 17. PMID:36806352 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Transducin 3D structures

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