Structure Report for: 4UUQ

Griebel, G., Pichat, P., Beeske, S., Leroy, T., Redon, N., Francon, D., Bert, L., Even, L., Lopez-Grancha, M., Tolstykh, T., Sun, F., Yu, Q., Brittain, S., Arlt, H., He, T., Zhang, B., Wiederschain, D., Bertrand, T., Houtman, J., Rak, A., Vallee, F., Michot, N., Auge, F., Menet, V., Bergis, O.E., George, P., Avenet, P., Mikol, V., Didier, M., Escoubet, J.

Title: Selective blockade of the hydrolysis of the endocannabinoid 2-arachidonoylglycerol impairs learning and memory performance while producing antinociceptive activity in rodents
Griebel G, Pichat P, Beeske S, Leroy T, Redon N, Jacquet A, Francon D, Bert L, Even L and Escoubet J <21 more author(s)> Griebel G, Pichat P, Beeske S, Leroy T, Redon N, Jacquet A, Francon D, Bert L, Even L, Lopez-Grancha M, Tolstykh T, Sun F, Yu Q, Brittain S, Arlt H, He T, Zhang B, Wiederschain D, Bertrand T, Houtmann J, Rak A, Vallee F, Michot N, Auge F, Menet V, Bergis OE, George P, Avenet P, Mikol V, Didier M, Escoubet J (- 21)
Ref: Sci Rep, 5:7642, 2015 : PubMed
Abstract


ESTHER: Griebel_2015_Sci.Rep_5_7642
PubMedSearch: Griebel 2015 Sci.Rep 5 7642
PubMedID: 25560837
Gene_locus related to this paper: mouse-ABHD6
Inhibitor(s) related to this paper: 64D

Abstract

Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects in assays of inflammatory and visceral pain. In addition, the drug alters learning performance in several assays related to episodic, working and spatial memory. Moreover, long term potentiation (LTP) of CA1 synaptic transmission and acetylcholine release in the hippocampus, two hallmarks of memory function, are both decreased by SAR127303. Although inactive in acute seizure tests, repeated administration of SAR127303 delays the acquisition and decreases kindled seizures in mice, indicating that the drug slows down epileptogenesis, a finding deserving further investigation to evaluate the potential of MAGL inhibitors as antiepileptics. However, the observation that 2-AG hydrolysis blockade alters learning and memory performance, suggests that such drugs may have limited value as therapeutic agents.



        

Title: Structural basis for human monoglyceride lipase inhibition
Bertrand T, Auge F, Houtmann J, Rak A, Vallee F, Mikol V, Berne PF, Michot N, Cheuret D and Mathieu M <1 more author(s)> Bertrand T, Auge F, Houtmann J, Rak A, Vallee F, Mikol V, Berne PF, Michot N, Cheuret D, Hoornaert C, Mathieu M (- 1)
Ref: Journal of Molecular Biology, 396:663, 2010 : PubMed
Abstract


ESTHER: Bertrand_2010_J.Mol.Biol_396_663
PubMedSearch: Bertrand 2010 J.Mol.Biol 396 663
PubMedID: 19962385
Gene_locus related to this paper: human-MGLL
Inhibitor(s) related to this paper: 2-methyl-pentane-2,4-diol, F4P

Abstract

Monoglyceride lipase (MGL) is a serine hydrolase that hydrolyses 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. 2-AG is an endogenous ligand of cannabinoid receptors, involved in various physiological processes in the brain. We present here the first crystal structure of human MGL in its apo form and in complex with the covalent inhibitor SAR629. MGL shares the classic fold of the alpha/beta hydrolase family but depicts an unusually large hydrophobic occluded tunnel with a highly flexible lid at its entry and the catalytic triad buried at its end. Structures reveal the configuration of the catalytic triad and the shape and nature of the binding site of 2-AG. The bound structure of SAR629 highlights the key interactions for productive binding with MGL. The shape of the tunnel suggests a high druggability of the protein and provides an attractive template for drug discovery.