6AX1
Structure of human monoacylglycerol lipase bound to a covalent inhibitor
Summary for 6AX1
| Entry DOI | 10.2210/pdb6ax1/pdb |
| Descriptor | Monoglyceride lipase, 1,1,1,3,3,3-hexafluoropropan-2-yl 3-(3-phenyl-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | monoacylglycerol lipase, covalent inhibitor, sbdd, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (Human) |
| Cellular location | Cytoplasm, cytosol : Q99685 |
| Total number of polymer chains | 2 |
| Total formula weight | 77584.17 |
| Authors | Pandit, J. (deposition date: 2017-09-06, release date: 2017-12-27, Last modification date: 2024-11-06) |
| Primary citation | Butler, C.R.,Beck, E.M.,Harris, A.,Huang, Z.,McAllister, L.A.,Am Ende, C.W.,Fennell, K.,Foley, T.L.,Fonseca, K.,Hawrylik, S.J.,Johnson, D.S.,Knafels, J.D.,Mente, S.,Noell, G.S.,Pandit, J.,Phillips, T.B.,Piro, J.R.,Rogers, B.N.,Samad, T.A.,Wang, J.,Wan, S.,Brodney, M.A. Azetidine and Piperidine Carbamates as Efficient, Covalent Inhibitors of Monoacylglycerol Lipase. J. Med. Chem., 60:9860-9873, 2017 Cited by PubMed Abstract: Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid (AA), a precursor to the proinflammatory eicosannoids such as prostaglandins. Herein we describe highly efficient MAGL inhibitors, identified through a parallel medicinal chemistry approach that highlighted the improved efficiency of azetidine and piperidine-derived carbamates. The discovery and optimization of 3-substituted azetidine carbamate irreversible inhibitors of MAGL were aided by the generation of inhibitor-bound MAGL crystal structures. Compound 6, a highly efficient and selective MAGL inhibitor against recombinant enzyme and in a cellular context, was tested in vivo and shown to elevate central 2-AG levels at a 10 mg/kg dose. PubMed: 29148769DOI: 10.1021/acs.jmedchem.7b01531 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.26 Å) |
Structure validation
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