8HQC

Structure of a GPCR-G protein in complex with a natural peptide agonist

Summary for 8HQC

• Entry DOI: 10.2210/pdb8hqc/pdb
• EMDB information: 34947
• Descriptor: C5a anaphylatoxin chemotactic receptor 1, Guanine nucleotide-binding protein G(o) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• Functional Keywords: gpcr, g protein, signaling protein, signaling protein-immune system complex, signaling protein/immune system
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 6
• Total formula weight: 154007.55

Authors

Saha, S.,Maharana, J.,Yadav, M.K.,Sarma, P.,Chami, M.,Banerjee, R.,Shukla, A.K. (deposition date: 2022-12-13, release date: 2023-10-18, Last modification date: 2024-10-30)

Primary citation

Yadav, M.K.,Maharana, J.,Yadav, R.,Saha, S.,Sarma, P.,Soni, C.,Singh, V.,Saha, S.,Ganguly, M.,Li, X.X.,Mohapatra, S.,Mishra, S.,Khant, H.A.,Chami, M.,Woodruff, T.M.,Banerjee, R.,Shukla, A.K.,Gati, C.
Molecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors.
Cell, 186:4956-4973.e21, 2023

PubMed Abstract: The complement system is a critical part of our innate immune response, and the terminal products of this cascade, anaphylatoxins C3a and C5a, exert their physiological and pathophysiological responses primarily via two GPCRs, C3aR and C5aR1. However, the molecular mechanism of ligand recognition, activation, and signaling bias of these receptors remains mostly elusive. Here, we present nine cryo-EM structures of C3aR and C5aR1 activated by their natural and synthetic agonists, which reveal distinct binding pocket topologies of complement anaphylatoxins and provide key insights into receptor activation and transducer coupling. We also uncover the structural basis of a naturally occurring mechanism to dampen the inflammatory response of C5a via proteolytic cleavage of the terminal arginine and the G-protein signaling bias elicited by a peptide agonist of C3aR identified here. In summary, our study elucidates the innerworkings of the complement anaphylatoxin receptors and should facilitate structure-guided drug discovery to target these receptors in a spectrum of disorders.

PubMed: 37852260
DOI: 10.1016/j.cell.2023.09.020

Experimental method

ELECTRON MICROSCOPY (3.89 Å)