Objective The cannabinoid CB1 receptor (CB1R) is an attractive molecular target for the treatment of substance abuse, drug addiction, schizophrenia, bipolar disorder, motor dysfunction including Huntington’s disease, as well as cardiometabolic disease and metabolic syndrome.The general aim of the project is to investigate in silico the phenomenon of the homodimerization of the CB1R, the interaction of the CB1R homodimer with ligands, and to study the effect of membrane cholesterol and the cannabinoid receptor interacting protein 1a, CRIP1a, on the functioning of the CB1R homodimer. The project is intended to verify a set of hypotheses: (i) homodimerization of the CB1R is agonist-mediated; (ii) the interface transmits cross-talk between protomers; (iii) cholesterol promotes CB1R homodimerization; (iv) cholesterol stabilizes the inactive state of the CB1R homodimer; (v) the CRIP1a stabilizes the inactive state of the CB1R monomer; (vi) the CRIP1a hampers CB1R homodimerization. The project involves the following detailed objectives:(1) homology modelling of the CB1R monomer in the active and inactive state;(2) application of protein-protein docking and surface roughness-based scoring to construct a model of the CB1R homodimer in the active, inactive and “mixed” state;(3) all-atom molecular dynamics (MD) simulations of respective dimers and monomers in a lipid bilayer;(4) all-atom MD simulations of the respective dimers and monomers in a lipid bilayer containing cholesterol;(5) modelling of CRIP1a;(6) modelling of the CB1R-CRIP1a complexes applying protein-protein docking and MD simulations;(7) coarse-grained MD to investigate the assembly of CB1R monomers and CB1R-CRIP1a complexes in a lipid bilayer;(8) coarse-grained MD to investigate the assembly of CB1R monomers and CB1R-CRIP1a complexes in a lipid bilayer containing cholesterol;(9) application of structure-based drug design methods to elaborate compounds that modulate dimer activity. Fields of science medical and health sciencesbasic medicinemedicinal chemistrynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesbiochemistrybiomoleculeslipidsmedical and health scienceshealth sciencessubstance abusemedical and health sciencesclinical medicinepsychiatryschizophrenia Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) FP7-PEOPLE-2011-IEF - Marie-Curie Action: "Intra-European fellowships for career development" Call for proposal FP7-PEOPLE-2011-IEF See other projects for this call Funding Scheme MC-IEF - Intra-European Fellowships (IEF) Coordinator ITA-SUOMEN YLIOPISTO Address Yliopistonranta 8 70211 Kuopio Finland See on map Region Manner-Suomi Pohjois- ja Itä-Suomi Pohjois-Savo Activity type Higher or Secondary Education Establishments Administrative Contact Tiina Reinikainen (Ms.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution No data
