8ia2
From Proteopedia
Structure of C5a bound human C5aR1 in complex with Go (Composite map)
Structural highlights
FunctionC5AR1_HUMAN Receptor for the chemotactic and inflammatory peptide anaphylatoxin C5a (PubMed:1847994, PubMed:8182049, PubMed:7622471, PubMed:9553099, PubMed:10636859, PubMed:15153520). The ligand interacts with at least two sites on the receptor: a high-affinity site on the extracellular N-terminus, and a second site in the transmembrane region which activates downstream signaling events (PubMed:8182049, PubMed:7622471, PubMed:9553099). Receptor activation stimulates chemotaxis, granule enzyme release, intracellular calcium release and superoxide anion production (PubMed:10636859, PubMed:15153520).[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe 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. Molecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors.,Yadav MK, Maharana J, Yadav R, Saha S, Sarma P, Soni C, Singh V, Saha S, Ganguly M, Li XX, Mohapatra S, Mishra S, Khant HA, Chami M, Woodruff TM, Banerjee R, Shukla AK, Gati C Cell. 2023 Oct 26;186(22):4956-4973.e21. doi: 10.1016/j.cell.2023.09.020. Epub , 2023 Oct 17. PMID:37852260[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Mus musculus | Banerjee R | Gati C | Maharana J | Shukla AK | Yadav MK | Yadav R
