title: Free-energy studies reveal a possible mechanism for oxidation-dependent inhibition of MGL.
abstract: The 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.
authors: Dipartimento di Farmacia, Università degli Studi di Parma, I-43124 Parma, Italy.
authors: Laura
authors: L
authors: Scalvini
authors: Dipartimento di Farmacia, Università degli Studi di Parma, I-43124 Parma, Italy.
authors: Federica
authors: F
authors: Vacondio
authors: Dipartimento di Farmacia, Università degli Studi di Parma, I-43124 Parma, Italy.
authors: Michele
authors: M
authors: Bassi
authors: Dipartimento di Farmacia, Università degli Studi di Parma, I-43124 Parma, Italy.
authors: Daniele
authors: D
authors: Pala
authors: Dipartimento di Farmacia, Università degli Studi di Parma, I-43124 Parma, Italy.
authors: Alessio
authors: A
authors: Lodola
authors: Dipartimento di Farmacia, Università degli Studi di Parma, I-43124 Parma, Italy.
authors: Silvia
authors: S
authors: Rivara
authors: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, United States.
authors: Kwang-Mook
authors: KM
authors: Jung
authors: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, United States.|Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, United States.|Unit of Drug Discovery and Development, Istituto Italiano di Tecnologia, I-16163, Genova, Italy.
authors: Daniele
authors: D
authors: Piomelli
authors: Dipartimento di Farmacia, Università degli Studi di Parma, I-43124 Parma, Italy.
authors: Marco
authors: M
authors: Mor
mesh_terms: D020134:Catalytic Domain; D003545:Cysteine / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D006861:Hydrogen Peroxide / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D008994:Monoacylglycerol Lipases / Q000737:chemistry*; D010084:Oxidation-Reduction; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D013816:Thermodynamics
chemical_list: D006861:Hydrogen Peroxide; D008994:Monoacylglycerol Lipases; D003545:Cysteine