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理解 VPAC 受体家族肽结合和选择性。

Understanding VPAC receptor family peptide binding and selectivity.

机构信息

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.

ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia.

出版信息

Nat Commun. 2022 Nov 16;13(1):7013. doi: 10.1038/s41467-022-34629-3.

DOI:10.1038/s41467-022-34629-3
PMID:36385145
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9668914/
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.

摘要

血管活性肠肽 (VIP) 和垂体腺苷酸环化酶激活肽 (PACAP) 受体是神经过程的关键调节因子。尽管有最近的结构数据，但对不同亚家族受体之间的肽结合和选择性的全面了解仍缺乏。在这里，我们确定了活性、Gs 偶联的 VIP-VPAC1R、PACAP27-VPAC1R 和 PACAP27-PAC1R 复合物的结构。冷冻电镜结构分析和分子动力学模拟 (MDS) 显示，与 PACAP27 相比，VPAC1R 与 VIP 之间的稳定相互作用较少，VIP 与细胞外环 3 的相互作用具有更大的动力学，以及保守的 N 端肽残基与受体核心之间的相互作用存在受体依赖性差异。将 VIP 模拟到 PAC1R 中的 MD 预测 VIP-PAC1R 相互作用在受体核心中比 VIP-VPAC1R 更短暂，这可能是 VIP 对 VPAC1R 的选择性高于 PAC1R 的基础。总的来说，我们的工作提高了对肽与 PAC1R 和 VPAC1R 结合的分子理解，这可能有利于新型选择性激动剂的开发。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1abf/9668914/32a470a723b1/41467_2022_34629_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1abf/9668914/b635953be27c/41467_2022_34629_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1abf/9668914/dcc9505f716f/41467_2022_34629_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1abf/9668914/7ad7c1ef5dd5/41467_2022_34629_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1abf/9668914/eae2609f70ad/41467_2022_34629_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1abf/9668914/ab65263350a5/41467_2022_34629_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1abf/9668914/32a470a723b1/41467_2022_34629_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1abf/9668914/b635953be27c/41467_2022_34629_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1abf/9668914/dcc9505f716f/41467_2022_34629_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1abf/9668914/7ad7c1ef5dd5/41467_2022_34629_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1abf/9668914/eae2609f70ad/41467_2022_34629_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1abf/9668914/ab65263350a5/41467_2022_34629_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1abf/9668914/32a470a723b1/41467_2022_34629_Fig6_HTML.jpg

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