title: Lid domain plasticity and lipid flexibility modulate enzyme specificity in human monoacylglycerol lipase.
abstract: Human monoacylglycerol lipase (MAGL) is a membrane-interacting enzyme that generates pro-inflammatory signaling molecules. For this reason, MAGL inhibition is a promising strategy to treat pain, cancer, and neuroinflammatory diseases. MAGL can hydrolyze monoacylglycerols bearing an acyl chain of different lengths and degrees of unsaturation, cleaving primarily the endocannabinoid 2-arachidonoylglycerol. Importantly, the enzymatic binding site of MAGL is confined by a 75-amino-acid-long, flexible cap domain, named 'lid domain', which is structurally similar to that found in several other lipases. However, it is unclear how lid domain plasticity affects catalysis in MAGL. By integrating extensive molecular dynamics simulations and free-energy calculations with mutagenesis and kinetic experiments, we here define a lid-domain-mediated mechanism for substrate selection and binding in MAGL catalysis. In particular, we clarify the key role of Phe159 and Ile179, two conserved residues within the lid domain, in regulating substrate specificity in MAGL. We conclude by proposing that other structurally related lipases may share this lid-domain-mediated mechanism for substrate specificity.
authors.affiliation: Laboratory of Molecular Modeling and Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy. Electronic address: laura.riccardi@iit.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Riccardi
authors.affiliation: Laboratory of Molecular Modeling and Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy. Electronic address: jose.arencibia@iit.it.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Arencibia
authors.affiliation: D3-PharmaChemistry, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy. Electronic address: luca.bono@iit.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Bono
authors.affiliation: D3-PharmaChemistry, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy. Electronic address: andrea.armirotti@iit.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.affiliation: CompuNet, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy. Electronic address: stefania.girotto@iit.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Girotto
authors.affiliation: Laboratory of Molecular Modeling and Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy; IAS-5/INM-9 Computational Biomedicine Forschungszentrum Jülich, Wilhelm-Johnen-Straße, 52428 Jülich, Germany. Electronic address: marco.devivo@iit.it.
authors.forename: Marco
authors.initials: M
authors.lastname: De Vivo
mesh_terms: D002384:Catalysis; D004791:Enzyme Inhibitors / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D008994:Monoacylglycerol Lipases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D050178:Monoglycerides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D050178:Monoglycerides; D008994:Monoacylglycerol Lipases
keywords: Lid domain; Molecular dynamics simulations; Monoacylglycerol lipase