Understanding VPAC receptor family peptide binding and selectivity

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 lacki...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
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Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9668914/
https://www.ncbi.nlm.nih.gov/pubmed/36385145
http://dx.doi.org/10.1038/s41467-022-34629-3
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author 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
author_facet 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
author_sort Piper, Sarah J.
collection PubMed
description 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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spelling pubmed-96689142022-11-18 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 Nat Commun Article 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. Nature Publishing Group UK 2022-11-16 /pmc/articles/PMC9668914/ /pubmed/36385145 http://dx.doi.org/10.1038/s41467-022-34629-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
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
Understanding VPAC receptor family peptide binding and selectivity
title Understanding VPAC receptor family peptide binding and selectivity
title_full Understanding VPAC receptor family peptide binding and selectivity
title_fullStr Understanding VPAC receptor family peptide binding and selectivity
title_full_unstemmed Understanding VPAC receptor family peptide binding and selectivity
title_short Understanding VPAC receptor family peptide binding and selectivity
title_sort understanding vpac receptor family peptide binding and selectivity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9668914/
https://www.ncbi.nlm.nih.gov/pubmed/36385145
http://dx.doi.org/10.1038/s41467-022-34629-3
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