7Y66

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

Summary for 7Y66

• Entry DOI: 10.2210/pdb7y66/pdb
• EMDB information: 33635
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: complex, agonist, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 155502.29

Authors

Feng, Y.Y.,Zhao, C.,Yan, W.,Shao, Z.H. (deposition date: 2022-06-18, release date: 2023-03-01, Last modification date: 2024-10-09)

Primary citation

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.
Mechanism of activation and biased signaling in complement receptor C5aR1.
Cell Res., 33:312-324, 2023

PubMed Abstract: 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 β-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 protein complex bound to each of the following: C5a, the hexapeptidic agonist C5a, 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 mutant-G 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 protein coupling of C5aR1, which may facilitate the future design of therapeutic agents.

PubMed: 36806352
DOI: 10.1038/s41422-023-00779-2

Experimental method

ELECTRON MICROSCOPY (2.9 Å)