Understanding VPAC receptor family peptide binding and selectivity

Sarah J. Piper, Giuseppe Deganutti, Jessica Lu, Peishen Zhao, Yi-Lynn Liang, Yao Lu, Madeleine M. Fletcher, Mohammed Akhter Hossain, Arthur Christopoulos, Christopher A. Reynolds, Radostin Danev, Patrick M. Sexton () and Denise Wootten ()
Additional contact information
Sarah J. Piper: Monash University
Giuseppe Deganutti: Coventry University
Jessica Lu: Monash University
Peishen Zhao: Monash University
Yi-Lynn Liang: Monash University
Yao Lu: Monash University
Madeleine M. Fletcher: Monash University
Mohammed Akhter Hossain: The University of Melbourne
Arthur Christopoulos: Monash University
Christopher A. Reynolds: Coventry University
Radostin Danev: University of Tokyo
Patrick M. Sexton: Monash University
Denise Wootten: Monash University

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34629-3

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DOI: 10.1038/s41467-022-34629-3

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