Understanding VPAC receptor family peptide binding and selectivity.

Pituitary Adenylate Cyclase-Activating Polypeptide / metabolism Vasoactive Intestinal Peptide / metabolism Protein Binding Molecular Dynamics Simulation

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
16 11 2022
Historique:
received: 16 01 2022
accepted: 01 11 2022
entrez: 17 11 2022
pubmed: 18 11 2022
medline: 22 11 2022
Statut: epublish

Résumé

The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) receptors are key regulators of neurological processes. Despite recent structural data, a comprehensive understanding of peptide binding and selectivity among different subfamily receptors is lacking. Here, we determine structures of active, Gs-coupled, VIP-VPAC1R, PACAP27-VPAC1R, and PACAP27-PAC1R complexes. Cryo-EM structural analyses and molecular dynamics simulations (MDSs) reveal fewer stable interactions between VPAC1R and VIP than for PACAP27, more extensive dynamics of VIP interaction with extracellular loop 3, and receptor-dependent differences in interactions of conserved N-terminal peptide residues with the receptor core. MD of VIP modelled into PAC1R predicts more transient VIP-PAC1R interactions in the receptor core, compared to VIP-VPAC1R, which may underlie the selectivity of VIP for VPAC1R over PAC1R. Collectively, our work improves molecular understanding of peptide engagement with the PAC1R and VPAC1R that may benefit the development of novel selective agonists.

Identifiants

DOI: 10.1038/s41467-022-34629-3 PMID: 36385145 PMC: PMC9668914
pubmed: 36385145
doi: 10.1038/s41467-022-34629-3
pii: 10.1038/s41467-022-34629-3
pmc: PMC9668914
doi:

Substances chimiques

Pituitary Adenylate Cyclase-Activating Polypeptide 0
Vasoactive Intestinal Peptide 37221-79-7

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

7013

Informations de copyright

© 2022. The Author(s).

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Auteurs

Sarah J Piper (SJ)

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
ORCID: 0000-0001-5337-5197

Giuseppe Deganutti (G)

Centre for Sport, Exercise and Life Sciences, Coventry University, CV1 5FB, Coventry, UK.
ORCID: 0000-0001-8780-2986

Jessica Lu (J)

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.

Peishen Zhao (P)

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
ORCID: 0000-0003-0185-0595

Yi-Lynn Liang (YL)

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
Confo TherapeuticsTechnologiepark 94, Ghent (Zwijnaarde), 9052, Belgium.

Yao Lu (Y)

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.

Madeleine M Fletcher (MM)

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
GlaxoSmithKline, Abbotsford, 3067, VIC, Australia.
ORCID: 0000-0001-5519-4832

Mohammed Akhter Hossain (MA)

Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3010, Australia.
ORCID: 0000-0002-9961-0006

Arthur Christopoulos (A)

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
ORCID: 0000-0003-4442-3294

Christopher A Reynolds (CA)

Centre for Sport, Exercise and Life Sciences, Coventry University, CV1 5FB, Coventry, UK.
School of Life Sciences, University of Essex, Wivenhoe Park, Colchester, CO4 3SQ, UK.
ORCID: 0000-0001-9267-5141

Radostin Danev (R)

Graduate School of Medicine, University of Tokyo, S402, 7-3-1 Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan.
ORCID: 0000-0001-6406-8993

Patrick M Sexton (PM)

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia. patrick.sexton@monash.edu.
ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia. patrick.sexton@monash.edu.
ORCID: 0000-0001-8902-2473

Denise Wootten (D)

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia. denise.wootten@monash.edu.
ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia. denise.wootten@monash.edu.
ORCID: 0000-0003-4563-1642

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Classifications MeSH

questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Facteurs de croissance nerveuse › Polypeptide activateur de l'adénylcyclase hypophysaire › Understanding VPAC receptor family peptide...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de tissu nerveux › Neuropeptides › Peptide vasoactif intestinal › Understanding VPAC receptor family peptide...
questionsmedicales.fr › Métabolisme › Liaison aux protéines › Understanding VPAC receptor family peptide...
questionsmedicales.fr › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de dynamique moléculaire › Understanding VPAC receptor family peptide...