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Understanding VPAC receptor family peptide binding and selectivity.
Piper, Sarah J; Deganutti, Giuseppe; Lu, Jessica; Zhao, Peishen; Liang, Yi-Lynn; Lu, Yao; Fletcher, Madeleine M; Hossain, Mohammed Akhter; Christopoulos, Arthur; Reynolds, Christopher A; Danev, Radostin; Sexton, Patrick M; Wootten, Denise.
Afiliação
  • Piper SJ; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
  • Deganutti G; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
  • Lu J; Centre for Sport, Exercise and Life Sciences, Coventry University, CV1 5FB, Coventry, UK.
  • Zhao P; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
  • Liang YL; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
  • Lu Y; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
  • Fletcher MM; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
  • Hossain MA; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
  • Christopoulos A; Confo TherapeuticsTechnologiepark 94, Ghent (Zwijnaarde), 9052, Belgium.
  • Reynolds CA; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
  • Danev R; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
  • Sexton PM; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.
  • Wootten D; GlaxoSmithKline, Abbotsford, 3067, VIC, Australia.
Nat Commun ; 13(1): 7013, 2022 11 16.
Article em En | MEDLINE | ID: mdl-36385145
ABSTRACT
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Peptídeo Intestinal Vasoativo / Polipeptídeo Hipofisário Ativador de Adenilato Ciclase Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Peptídeo Intestinal Vasoativo / Polipeptídeo Hipofisário Ativador de Adenilato Ciclase Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2022 Tipo de documento: Article