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.

Free-energy studies reveal a possible mechanism for oxidation-dependent inhibition of MGL / Scalvini, Laura; Vacondio, Federica; Bassi, Michele; Pala, Daniele; Lodola, Alessio; Rivara, Silvia; Jung, Kwang Mook; Piomelli, Daniele; Mor, Marco. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 6:(2016), pp. 1-12. [10.1038/srep31046]

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

SCALVINI, Laura;VACONDIO, Federica;BASSI, Michele;PALA, Daniele;LODOLA, Alessio;RIVARA, Silvia;MOR, Marco
2016-01-01

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.
2016
Free-energy studies reveal a possible mechanism for oxidation-dependent inhibition of MGL / Scalvini, Laura; Vacondio, Federica; Bassi, Michele; Pala, Daniele; Lodola, Alessio; Rivara, Silvia; Jung, Kwang Mook; Piomelli, Daniele; Mor, Marco. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 6:(2016), pp. 1-12. [10.1038/srep31046]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2818255
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