Molecular Basis of the PAC1 Receptor, a Stress-Related Membrane Protein

Jianing Li

Department of Chemistry, University of Vermont, Burlington, Vermont, USA

G-protein coupled receptors (GPCRs) are membrane proteins crucial for signal transduction in cells. They represent a family of current major therapeutic targets for new drug development. Despite the exceptional pharmaceutical importance, structure-based GPCR ligand development is still challenging — mainly due to limited knowledge about the three-dimensional structures and their activation/deactivation mechanisms. Recently a Class B GPCR for the endogenous PACAP neuropeptide, the PAC1 receptor, has attracted widespread interest as an emerging target for stress-related diseases. In an earlier study, we examined the open and closed PAC1 conformations interconnected within an ensemble of transitional states. The transition between the open and closed states are 10-30 times longer than those within the metastable closed states, which clearly implicate allosteric effects propagating through the protein. In our recent study, it is suggested that with the PACAP neuropeptide bound to the extracellular domain, the PAC1 receptor undergoes a conformational change to insert the peptide into the orthosteric binding site in the protein. With simulation and experimental evidence, five Nterminal residues of PACAP are found crucial to disrupt the interaction network within the receptor, and eventually lead to the opening of the G-protein binding site. Coherent movements of the PAC1 transmembrane helices are illustrated in detail by conventional and free-energy molecular simulations. All these findings provide structural and mechanistic insights for the activation and modulation of the PAC1 receptor and related Class B receptors, leading to aid the discovery of two small-molecule antagonists with potential anti-stress activity.