Molecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors.

Anaphylatoxins / metabolism Complement C3a / metabolism Immunity, Innate Receptors, Complement / metabolism Signal Transduction Humans Animals Mice
GPCRs anaphylatoxins arrestin-coupled receptors beta-arrestins cellular signaling complement cascade complement receptors cryo-EM drug discovery signaling bias

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
26 10 2023
Historique:
received: 15 02 2023
revised: 19 07 2023
accepted: 20 09 2023
medline: 30 10 2023
pubmed: 19 10 2023
entrez: 18 10 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.cell.2023.09.020 PMID: 37852260
pubmed: 37852260
pii: S0092-8674(23)01074-7
doi: 10.1016/j.cell.2023.09.020
pii:
doi:

Substances chimiques

Anaphylatoxins 0
Complement C3a 80295-42-7
Receptors, Complement 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

4956-4973.e21

Subventions

Organisme : NIGMS NIH HHS
ID : R01 GM144965
Pays : United States

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

Auteurs

Manish K Yadav (MK)

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.

Jagannath Maharana (J)

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.

Ravi Yadav (R)

Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA; The Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.

Shirsha Saha (S)

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.

Parishmita Sarma (P)

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.

Chahat Soni (C)

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.

Vinay Singh (V)

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.

Sayantan Saha (S)

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.

Manisankar Ganguly (M)

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.

Xaria X Li (XX)

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072, Australia.

Samanwita Mohapatra (S)

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.

Sudha Mishra (S)

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.

Htet A Khant (HA)

USC Center of Excellence for Nano-Imaging, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA.

Mohamed Chami (M)

BioEM Lab, Biozentrum, Universität Basel, Basel, Switzerland.

Trent M Woodruff (TM)

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072, Australia.

Ramanuj Banerjee (R)

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India. Electronic address: ramanujb@iitk.ac.in.

Arun K Shukla (AK)

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India. Electronic address: arshukla@iitk.ac.in.

Cornelius Gati (C)

Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA; The Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA; Department of Chemistry, Department of Quantitative and Computational Biology, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, USA. Electronic address: gati@usc.edu.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du sang › Immunoprotéines › Protéines du système du complément › Anaphylatoxines › Molecular basis of anaphylatoxin binding,...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du sang › Immunoprotéines › Protéines du système du complément › Complément C3 › Complément C3a › Molecular basis of anaphylatoxin binding,...
questionsmedicales.fr › Phénomènes du système immunitaire › Immunité › Immunité innée › Molecular basis of anaphylatoxin binding,...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs immunologiques › Récepteurs au complément › Molecular basis of anaphylatoxin binding,...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Molecular basis of anaphylatoxin binding,...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Molecular basis of anaphylatoxin binding,...
questionsmedicales.fr › Eucaryotes › Animaux › Molecular basis of anaphylatoxin binding,...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Molecular basis of anaphylatoxin binding,...