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, Denise Wootten

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    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.
    Original languageEnglish
    Article number7013
    Number of pages20
    JournalNature Communications
    Publication statusPublished - 16 Nov 2022

    Bibliographical note

    Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.


    Funding Information: This work was supported by the National Health and Medical Research Council of Australia (NHMRC) (program grant 1150083, P.M.S./A.C.; Senior Research Fellowship 1155302, D.W.; Senior Principal Research Fellowship 1154434, P.M.S.). R.D. was supported by Takeda Science Foundation 2019 Medical Research Grant and Japan Science and Technology Agency PRESTO (18069571). C.A.R is grateful for a Royal Society Industry Fellowship. This work was supported by the Monash University Ramaciotti Centre for cryo-electron microscopy (negative staining TEM) and the Monash University MASSIVE high-performance computing facility (cryo-EM data processing). The authors would like to thank Yan Zhang, H. Eric Xu and Yi Jiang for providing access to their structural data for VPAC1R prior to publication, George Christopoulos and Villy Julita for generating the expression constructs and alanine mutants of the PAC1R and VPAC1R, as well as Rachel M. Johnson and Matthew J. Belousoff for assisting with map and model refinements and validation. Funding Information: Interactions between chains were analyzed using the “Dimplot” module within the Ligplot+ program (v2.2) (, Supplementary Fig. ). Hydrogen bonds were also assessed using the UCSF ChimeraX package, with relaxed distance and angle criteria (0.4 Å and 20-degree tolerance, respectively; Table , Fig. , Supplementary Figs. , ). Visualization of structures and production of images was performed using the UCSF Chimera package (v1.14) from the Computer Graphics Laboratory, University of California, San Francisco (supported by NIH P41 RR-01081) and ChimeraX (support from National Institutes of Health R01-GM129325). For comparison of complex structures, unless otherwise stated, complexes were aligned by receptor chains using the matchmaker command in Chimera/ChimeraX. Publisher Copyright: © 2022, The Author(s).


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


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