caa a22 4500 467938628 CHVBK 20180406153005.0 cr unu---uuuuu 170328e20060801xx s 000 0 eng 10.1007/s10822-006-9064-0 doi (NATIONALLICENCE)springer-10.1007/s10822-006-9064-0 Inactive and active states and supramolecular organization of GPCRs: insights from computational modeling [Elektronische Daten] [Francesca Fanelli, Pier De Benedetti] Herein we make an overview of the results of our computational experiments aimed at gaining insight into the molecular mechanisms of GPCR functioning either in their normal conditions or when hit by gain-of-function or loss-of-function mutations. Molecular simulations of a number of GPCRs in their wild type and mutated as well as free and ligand-bound forms were instrumental in inferring the structural features, which differentiate the mutation- and ligand-induced active from the inactive states. These features essentially reside in the interaction pattern of the E/DRY arginine and in the degree of solvent exposure of selected cytosolic domains. Indeed, the active states differ from the inactive ones in the weakening of the interactions made by the highly conserved arginine and in the increase in solvent accessibility of the cytosolic interface between helices 3 and 6. Where possible, the structural hallmarks of the active and inactive receptor states are translated into molecular descriptors useful for in silico functional screening of novel receptor mutants or ligands. Computational modeling of the supramolecular organization of GPCRs and their intracellular partners is the current challenge toward a deep understanding of their functioning mechanisms. Springer Science+Business Media B.V., 2006 GPCRs nationallicence G proteins nationallicence Constitutively active mutants nationallicence Comparative modeling nationallicence Molecular dynamics nationallicence Protein-protein docking nationallicence Molecular recognition nationallicence Fanelli Francesca Dulbecco Telethon Institute, University of Modena and Reggio Emilia, Via Campi 183, 41100, Modena, Italy aut De Benedetti Pier Department of Chemistry, University of Modena and Reggio Emilia, Via Campi 183, 41100, Modena, Italy aut Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/7-8(2006-08-01), 449-461 0920-654X 20:7-8<449 2006 20 10822 https://doi.org/10.1007/s10822-006-9064-0 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10822-006-9064-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Fanelli Francesca Dulbecco Telethon Institute, University of Modena and Reggio Emilia, Via Campi 183, 41100, Modena, Italy aut NATIONALLICENCE 700 1- De Benedetti Pier Department of Chemistry, University of Modena and Reggio Emilia, Via Campi 183, 41100, Modena, Italy aut NATIONALLICENCE 773 0- Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/7-8(2006-08-01), 449-461 0920-654X 20:7-8<449 2006 20 10822 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer