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TitleMolecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors.
Journal, issue, pagesCell, Vol. 186, Issue 22, Page 4956-4973.e21, Year 2023
Publish dateOct 26, 2023
AuthorsManish K Yadav / Jagannath Maharana / Ravi Yadav / Shirsha Saha / Parishmita Sarma / Chahat Soni / Vinay Singh / Sayantan Saha / Manisankar Ganguly / Xaria X Li / Samanwita Mohapatra / Sudha Mishra / Htet A Khant / Mohamed Chami / Trent M Woodruff / Ramanuj Banerjee / Arun K Shukla / Cornelius Gati /
PubMed AbstractThe 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 ...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.
External linksCell / PubMed:37852260
MethodsEM (single particle)
Resolution2.88 - 4.55 Å
Structure data

EMDB-35257, PDB-8i95:
Structure of EP54-C3aR-Go complex
Method: EM (single particle) / Resolution: 2.88 Å

EMDB-35259, PDB-8i97:
Structure of Apo-C3aR-Go complex (Glacios)
Method: EM (single particle) / Resolution: 3.19 Å

EMDB-35263, PDB-8i9a:
Structure of EP54-C3aR-Gq complex
Method: EM (single particle) / Resolution: 3.57 Å

EMDB-35275, PDB-8i9l:
Structure of C3a-C3aR-Go complex (Composite map)
Method: EM (single particle) / Resolution: 3.18 Å

EMDB-35282, PDB-8i9s:
Structure of Apo-C3aR-Go complex (Titan)
Method: EM (single particle) / Resolution: 3.26 Å

EMDB-35292, PDB-8ia2:
Structure of C5a bound human C5aR1 in complex with Go (Composite map)
Method: EM (single particle) / Resolution: 3.21 Å

EMDB-35293: C3a-C3aR-Go (C3aR-Go complex only, Original Map)
Method: EM (single particle) / Resolution: 3.18 Å

EMDB-35294: C3a-C3aR-Go (C3a only, Original Map)
Method: EM (single particle) / Resolution: 4.55 Å

EMDB-35295: C5a-hC5aR1-Go (hC5aR1-Go complex only, Original map)
Method: EM (single particle) / Resolution: 3.21 Å

EMDB-35296: C5a-hC5aR1-Go complex (C5a only, Original map)
Method: EM (single particle) / Resolution: 3.88 Å

EMDB-36001, PDB-8j6d:
Structure of EP141-C3aR-Go complex
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-36755, PDB-8jzz:
Structure of human C5a-desArg bound human C5aR1 in complex with Go
Method: EM (single particle) / Resolution: 3.31 Å

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / GPCR / G protein / SIGNALING PROTEIN-IMMUNE SYSTEM complex / SIGNALING PROTEIN / Cell Signaling / Immune system

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