Role of Second Extracellular Loop in the Function of Human Vasoactive Intestinal Polypeptide/Pituitary Adenylate Cyclase Activating Polypeptide Receptor 1 (hVPAC1R)

2000 ◽  
Vol 14 (3) ◽  
pp. 137-146 ◽  
Author(s):  
Sanne Møller Knudsen ◽  
Jeppe Wegener Tams ◽  
Jan Fahrenkrug
Keyword(s):  
Adenylate Cyclase ◽  
Vasoactive Intestinal Polypeptide ◽  
Extracellular Loop ◽  
Pituitary Adenylate Cyclase ◽  
Intestinal Polypeptide

Phospholipids stabilize binding of pituitary adenylate cyclase-activating peptide to vasoactive intestinal polypeptide receptor

2021 ◽  
Author(s):  
Nidhin Thomas ◽  
Ashutosh Agrawal
Keyword(s):  
Adenylate Cyclase ◽  
Receptor Binding ◽  
Vasoactive Intestinal Polypeptide ◽  
Binding Free Energy ◽  
Active Role ◽  
Lipid Binding ◽  
Peripheral Tissues ◽  
Peptide Receptor ◽  
Pituitary Adenylate Cyclase ◽  
Intestinal Polypeptide

Vasoactive intestinal polypeptide receptor (VIP1R) is a class B G-protein coupled receptor (GPCR) that is widely distributed throughout the central nervous system, T-lymphocytes, and peripheral tissues of organs like lungs and liver. Critical functions of these receptors render them potential pharmacological targets for the treatment of a broad spectrum of inflammatory and neurodegenerative diseases. Here we use atomistic studies to show that phospholipids can act as potent regulators of peptide binding on to the receptor. We simulated the binding of neuropeptide pituitary adenylate cyclase-activating peptide (PACAP27) into the transmembrane bundle of the receptor. The simulations reveal two lipid binding sites on the peptidic ligand for the negatively charged phosphodiester of phospholipids in the extracellular leaflet which lower the peptide-receptor binding free energy by ~8kBT. We further simulated the effect of anionic lipids phosphatidylinositol-4,5-bisphosphate (PIP2). These lipids show much stronger interaction, lowering the peptide-receptor binding energy by an additional ~7kBT compared to POPC lipids. These findings suggest that lipids can play an active role in catalyzing peptide-receptor binding and activating vasoactive intestinal polypeptide receptors.

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