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Understanding VPAC receptor family peptide binding and selectivity.

<div class='caption-title'>Overview of active, Gs-coupled PACAP family complexes solved using cryo-EM.</div>
<div class='caption-title'>Hydrogen bonds between peptide (P) and receptor (R) residues in the static structures.</div>
<div class='caption-title'>Dynamic analyses of receptor-peptide complexes by cryo-EM 3D variability analysis and MD simulations.</div>
Piper SJ, Deganutti G, Lu J, Zhao P, Liang YL, Lu Y, Fletcher MM, Hossain MA, Christopoulos A, Reynolds CA, Danev R, Sexton PM, Wootten D
OpenAccess logo Nat Commun 13 7013 (2022)
Related entries: 8e3x, 8e3y

Cited: 2 times
EuropePMC logo PMID: 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.

Articles citing this publication (2)

  1. Differential Responses of the GLP-1 and GLP-2 Receptors to N-Terminal Modification of a Dual Agonist. Gibadullin R, Cary BP, Gellman SH. J Am Chem Soc 145 12105-12114 (2023)
  2. Impact of secretin receptor homo-dimerization on natural ligand binding. Harikumar KG, Piper SJ, Christopoulos A, Wootten D, Sexton PM, Miller LJ. Nat Commun 15 4390 (2024)


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