Sandbox Reserved 919: Difference between revisions
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Bertrand, et al, created the first crystal structure of MGL in its <scene name='57/573133/Generic_monomer/3'>apo form</scene>. MGL is a part of the α-β hydrolase family of enzymes. This category of proteins contains an eight-stranded [http://en.wikipedia.org/wiki/Beta_sheet beta sheet], specifically containing seven parallel and one antiparallel constituent strand (<scene name='57/573134/Beta_sheet/1'>beta sheets</scene>), surrounded by [http://en.wikipedia.org/wiki/Alpha_helix alpha-helices]. <ref name="bert" /> | Bertrand, et al, created the first crystal structure of MGL in its <scene name='57/573133/Generic_monomer/3'>apo form</scene>. MGL is a part of the α-β hydrolase family of enzymes. This category of proteins contains an eight-stranded [http://en.wikipedia.org/wiki/Beta_sheet beta sheet], specifically containing seven parallel and one antiparallel constituent strand (<scene name='57/573134/Beta_sheet/1'>beta sheets</scene>), surrounded by [http://en.wikipedia.org/wiki/Alpha_helix alpha-helices]. <ref name="bert" /> | ||
MGL has a characteristic lid domain comprised of two large loops that surround <scene name='57/573134/Helix_a4/1'>helix A4</scene>. This region of the enzyme is the putative membrane-interacting moiety of the protein, which is consistent with its [http://en.wikipedia.org/wiki/Amphiphile amphipathic] nature and outward-facing hydrophobic residues. It has been proposed that 2-AG and other lipids suspended in the hydrophobic section of the cell membrane associate with this region before entering the active tunnel. Interestingly, MGL’s lid domain may be more flexible than its analogs in other α-β hydrolases, due to the various conformations it assumed in [http://en.wikipedia.org/wiki/Crystallography crystallographic studies]. <ref name="bert" /> Currently, there is no consensus about the quaternary arrangement of MGL. Some researchers claim that it is found as a monomer <ref name="bert" /> <ref name="shalk"> PMID:21308848 </ref>, whereas others believe it to be a physiologically active dimer. <ref name="labar"> PMID:19957260 </ref> | |||
MGL contains an active site tunnel roughly 25Å long and 8Å wide residing beneath its lid region. Like its substrate, 2-AG and other [http://en.wikipedia.org/wiki/Monoglyceride monoacylglycerols], the tunnel is largely amphipathic. Hydrophobic residues dominate the tunnel except for the terminal occluded region, which houses the [http://en.wikipedia.org/wiki/Catalytic_triad#Ser-His-Asp catalytic triad]. In its apo form, the catalytic region is not solvent-exposed, unlike the wide opening of the tunnel. <ref name="bert" /><ref name="labar" /> A unique structural motif in MGL is a 5Å solvent-exposed hole connecting the exterior to the catalytic site. It is proposed to act as an “exit hole” through which the glycerol product leaves MGL. The fatty acid product, namely arachidonic acid, presumably travels back through the active site tunnel. <ref name="bert" /><ref name="shalk" /><ref name="labar" /> | |||
===Active Site=== | ===Active Site=== | ||
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Monoglyceride LipaseMonoglyceride Lipase
IntroductionIntroduction
Monoglyceride Lipase (MGL, MAGL, MGLL) is a 33 kDa protein found mostly in the cell membrane. It is a serine hydrolase enzyme that exhibits an α/β hydrolase fold. In addition, MGL possesses amphitropic character, where the area around the active site of MGL is polar while the site itself is non-polar. This characteristic allows the protein to be present both in the membrane and in the cytosol. MGL plays a key role in the hydrolysis of 2-arachidonoylglycerol (2-AG), an endocannabinoid produced by the the central nervous system. The α/β fold allows 2-AG to selectively bind to the active site and be broken down into arachidonic acid and glycerol. Upon breakdown, glycerol leaves via an "exit tunnel" found perpendicular to the α/β fold. 2-AG itself has been found to possess anti-nociceptive, immunomodulatory, anti-inflammatory and tumor-reductive character when it binds to cannabinoid receptors. Due to the vast medical and therapeutic utility of 2-AG, the inhibition of MGL is a high interest target in pharmaceutical research. [1]
StructureBertrand, et al, created the first crystal structure of MGL in its . MGL is a part of the α-β hydrolase family of enzymes. This category of proteins contains an eight-stranded beta sheet, specifically containing seven parallel and one antiparallel constituent strand (), surrounded by alpha-helices. [1] MGL has a characteristic lid domain comprised of two large loops that surround . This region of the enzyme is the putative membrane-interacting moiety of the protein, which is consistent with its amphipathic nature and outward-facing hydrophobic residues. It has been proposed that 2-AG and other lipids suspended in the hydrophobic section of the cell membrane associate with this region before entering the active tunnel. Interestingly, MGL’s lid domain may be more flexible than its analogs in other α-β hydrolases, due to the various conformations it assumed in crystallographic studies. [1] Currently, there is no consensus about the quaternary arrangement of MGL. Some researchers claim that it is found as a monomer [1] [2], whereas others believe it to be a physiologically active dimer. [3] MGL contains an active site tunnel roughly 25Å long and 8Å wide residing beneath its lid region. Like its substrate, 2-AG and other monoacylglycerols, the tunnel is largely amphipathic. Hydrophobic residues dominate the tunnel except for the terminal occluded region, which houses the catalytic triad. In its apo form, the catalytic region is not solvent-exposed, unlike the wide opening of the tunnel. [1][3] A unique structural motif in MGL is a 5Å solvent-exposed hole connecting the exterior to the catalytic site. It is proposed to act as an “exit hole” through which the glycerol product leaves MGL. The fatty acid product, namely arachidonic acid, presumably travels back through the active site tunnel. [1][2][3] Active Site
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ReferencesReferences
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Bertrand T, Auge F, Houtmann J, Rak A, Vallee F, Mikol V, Berne PF, Michot N, Cheuret D, Hoornaert C, Mathieu M. Structural basis for human monoglyceride lipase inhibition. J Mol Biol. 2010 Feb 26;396(3):663-73. Epub 2009 Dec 3. PMID:19962385 doi:10.1016/j.jmb.2009.11.060
- ↑ 2.0 2.1 Schalk-Hihi C, Schubert C, Alexander R, Bayoumy S, Clemente JC, Deckman I, Desjarlais RL, Dzordzorme KC, Flores CM, Grasberger B, Kranz JK, Lewandowski F, Liu L, Ma H, Maguire D, Macielag MJ, McDonnell ME, Haarlander TM, Miller R, Milligan C, Reynolds C, Kuo LC. Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 A resolution. Protein Sci. 2011 Feb 3. doi: 10.1002/pro.596. PMID:21308848 doi:10.1002/pro.596
- ↑ 3.0 3.1 3.2 Labar G, Bauvois C, Borel F, Ferrer JL, Wouters J, Lambert DM. Crystal structure of the human monoacylglycerol lipase, a key actor in endocannabinoid signaling. Chembiochem. 2010 Jan 25;11(2):218-27. PMID:19957260 doi:10.1002/cbic.200900621