ArticleFrontiers in molecular biosciences2021
Molecular Basis of Class B GPCR Selectivity for the Neuropeptides PACAP and VIP.
Article in Frontiers in molecular biosciences, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
15 citing papers in PubMed.
- Article
- Evaluation of Essential Dynamics and Fixed-Length Coarse Graining for Multidomain Proteins.The journal of physical chemistry. B · 2024Article
- Heparin Oligosaccharides as Vasoactive Intestinal Peptide Inhibitors via their Binding Process Characterization.Current protein & peptide science · 2024Article
- Constitutive and conditional deletion reveals distinct phenotypes driven by developmental versus neurotransmitter actions of the neuropeptide PACAP.Journal of neuroendocrinology · 2023Article
- PACAP and VIP Neuropeptides' and Receptors' Effects on Appetite, Satiety and Metabolism.Biology · 2023Review
- GPCRLigNet: rapid screening for GPCR active ligands using machine learning.Journal of computer-aided molecular design · 2023Article
- Understanding VPAC receptor family peptide binding and selectivity.Nature communications · 2022Article
- GPCR Intracellular Loop Regulation of Beta-Arrestin-Mediated Endosomal Signaling Dynamics.Journal of molecular neuroscience : MN · 2022Article
- Investigation of the Role of Pituitary Adenylate Cyclase-Activating Peptide (PACAP) and Its Type 1 (PAC1) Receptor in Uterine Contractility during Endometritis in Pigs.International journal of molecular sciences · 2022Article
- Pituitary adenylate cyclase-activating polypeptide receptor activation in the hypothalamus recruits unique signaling pathways involved in energy homeostasis.American journal of physiology. Endocrinology and metabolism · 2022Article
- Essential Dynamics Ensemble Docking for Structure-Based GPCR Drug Discovery.Frontiers in molecular biosciences · 2022Article
- Development of enhanced conformational sampling methods to probe the activation landscape of GPCRs.Advances in protein chemistry and structural biology · 2022Review
- Delineating the activation mechanism and conformational landscape of a class B G protein-coupled receptor glucagon receptor.Computational and structural biotechnology journal · 2022Article
- Recent Advances in Structure, Function, and Pharmacology of Class A Lipid GPCRs: Opportunities and Challenges for Drug Discovery.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Physiological and Pathological Processes within the Gastrointestinal Tract: A Review.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
The related neuropeptides PACAP and VIP, and their shared PAC1, VPAC1 and VPAC2 receptors, regulate a large array of physiological activities in the central and peripheral nervous systems. However, the lack of comparative and molecular mechanistic investigations hinder further understanding of their preferred binding selectivity and function. PACAP and VIP have comparable affinity at the VPAC1 and VPAC2 receptor, but PACAP is 400-1,000 fold more potent than VIP at the PAC1 receptor. A molecular understanding of the differing neuropeptide-receptor interactions and the details underlying the receptor transitions leading to receptor activation are much needed for the rational design of selective ligands. To these ends, we have combined structural information and advanced simulation techniques to study PACAP/VIP binding selectivity, full-length receptor conformation ensembles and transitions of the PACAP/VIP receptor variants and subtypes, and a few key interactions in the orthosteric-binding pocket. Our results reveal differential peptide-receptor interactions (at the atomistic detail) important for PAC1, VPAC1 and VPAC2 receptor ligand selectivity. Using microsecond-long molecular dynamics simulations and the Markov State Models, we have also identified diverse receptor conformational ensembles and microstate transition paths for each receptor, the potential mechanisms underlying receptor open and closed states, and the interactions and dynamics at the transmembrane orthosteric pocket for receptor activation. These analyses reveal important features in class B GPCR structure-dynamics-function relationships, which provide novel insights for structure-based drug discovery.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.