6533b823fe1ef96bd127ec85

RESEARCH PRODUCT

Free-energy studies reveal a possible mechanism for oxidation-dependent inhibition of MGL

Daniele PiomelliDaniele PiomelliSilvia RivaraLaura ScalviniFederica VacondioKwang-mook JungMarco MorMichele BassiAlessio LodolaDaniele Pala

subject

0301 basic medicineOxidative phosphorylationMolecular Dynamics SimulationRedoxArticle03 medical and health scienceschemistry.chemical_compoundCatalytic DomainHumansCysteineHydrogen peroxideMultidisciplinary030102 biochemistry & molecular biologybiologyHydrogen bondMetadynamicsActive siteSubstrate (chemistry)Hydrogen BondingHydrogen PeroxideMonoacylglycerol LipasesMonoacylglycerol lipase030104 developmental biologyBiochemistrychemistrybiology.proteinBiophysicsThermodynamicsOxidation-ReductionProtein Processing Post-TranslationalProtein Binding

description

AbstractThe function of monoacylglycerol lipase (MGL), a key actor in the hydrolytic deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2AG), is tightly controlled by the cell’s redox state: oxidative signals such as hydrogen peroxide suppress MGL activity in a reversible manner through sulfenylation of the peroxidatic cysteines, C201 and C208. Here, using as a starting point the crystal structures of human MGL (hMGL), we present evidence from molecular dynamics and metadynamics simulations along with high-resolution mass spectrometry studies indicating that sulfenylation of C201 and C208 alters the conformational equilibrium of the membrane-associated lid domain of MGL to favour closed conformations of the enzyme that do not permit the entry of substrate into the active site.

yearjournalcountryeditionlanguage
2016-08-08Scientific Reports
https://doi.org/10.1038/srep31046