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== Catalytic triad == | == Catalytic triad == | ||
MGL has a classic <scene name='58/580298/Catalytic_triad/1'>catalytic triad</scene> that contains Ser-His-Asp ('''figure 1'''). The triad was found using site-directed mutagenesis of each individual residue and each of these amino acid residues are catalytically essential to MGL <ref name="Bertrand" />. The catalytic triad is located in the binding pocket buried at the bottom of it in the oxyanion hole connected by a water molecule. This triad has a natural attraction to Endocannabinoids, specifically 2-arachidonylglycerol (2-AG) | MGL has a classic <scene name='58/580298/Catalytic_triad/1'>catalytic triad</scene> that contains Ser-His-Asp ('''figure 1'''). The triad was found using site-directed mutagenesis of each individual residue and each of these amino acid residues are catalytically essential to MGL <ref name="Bertrand" />. The catalytic triad is located in the binding pocket buried at the bottom of it in the oxyanion hole connected by a water molecule. [[Image:Catalytic_triad_binding_pocket.png]] | ||
This triad has a natural attraction to Endocannabinoids, specifically 2-arachidonylglycerol (2-AG) <ref name="Bertrand" />. | |||
====Binding==== | ====Binding==== | ||
2-AG binds to the catalytic triad and is hydrolyzed. The structure of 2-AG contains a long and flexible aliphatic chain and a polar head that is cleaved. 2-AG is broken down into arachidonic acid and glycerol which makes 2-AG inactive. '''See Overall Reaction.''' | 2-AG binds to the catalytic triad and is hydrolyzed. The structure of 2-AG contains a long and flexible aliphatic chain and a polar head that is cleaved. 2-AG is broken down into arachidonic acid and glycerol which makes 2-AG inactive. '''See Overall Reaction.''' | ||
===Inhibition of Catalytic Triad=== | ===Inhibition of Catalytic Triad=== | ||
Research on MGL is being geared towards inhibiting 2-AG from binding to the catalytic triad and being hydrolyzed. The binding of 2-AG to the catalytic triad | Research on MGL is being geared towards inhibiting 2-AG from binding to the catalytic triad and being hydrolyzed. The binding of 2-AG to the catalytic triad can be extracted before being hydrolyzed. MPD (2-methyl-pentane-2,4-diol)is located at the end of the tunnel where the catalytic triad is at and the tunnel is filled with MPD molecules. MPD being in the same vicinity will extract 2-AG from the triad and the MPD molecule will sit in there in place of 2-AG. This is a natural inhibition phenomenon. Inhibition of MGL leads to increase in 2-AG levels since AG is broken down by MGL <ref name="Clemente" />. The catalytic triad is a major part of MGL and its interaction with other parts within the brain and how the brain functions. | ||
==Ligand Binding Site== | ==Ligand Binding Site== | ||
[[Image:Overall_ligand.png|left|200px|thumb|Ligand within the Overall Structure of MGL]] | [[Image:Overall_ligand.png|left|200px|thumb|Ligand within the Overall Structure of MGL]] | ||
The <scene name='58/580298/Ligand/1'>ligand binding pocket</scene> of MGL has a large hydrophobic region with a polar bottom. The entrance of the binding pocket for MGL contains a lid, which is very flexible. The binding pocket or tunnel within MGL matches with the overall structure of 2-AG, with 2-AG's polar head being cleaved by the catalytic triad. Bertrand found that in MGL the binding pocket is not adjusted to the ligand's shape. However, the main movements of MGL associated with ligand binding involved the lid region. When 2-AG and its isomer 1(3)-AG bind to MGL, the hydrophobic chain is first aligned with the left part of the binding pocket. The carbonyl is then hydrogen bonded to <scene name='58/580298/Ala61/1'>Ala61</scene>. The polar head group of the ligand is then fixed by three hydrogen bonds. As a result, future research is looking into the large lipophilic portion of the binding pocket for designing selective inhibitors <ref name="Bertrand" />. | The <scene name='58/580298/Ligand/1'>ligand binding pocket</scene> of MGL has a large hydrophobic region with a polar bottom. The entrance of the binding pocket for MGL contains a lid, which is very flexible. The binding pocket or tunnel within MGL matches with the overall structure of 2-AG, with 2-AG's polar head being cleaved by the catalytic triad. Bertrand found that in MGL the binding pocket is not adjusted to the ligand's shape. However, the main movements of MGL associated with ligand binding involved the lid region. When 2-AG and its isomer 1(3)-AG bind to MGL, the hydrophobic chain is first aligned with the left part of the binding pocket. The carbonyl is then hydrogen bonded to <scene name='58/580298/Ala61/1'>Ala61</scene>. The polar head group of the ligand is then fixed by three hydrogen bonds. As a result, future research is looking into the large lipophilic portion of the binding pocket for designing selective inhibitors <ref name="Bertrand" />. | ||
==Overall Reaction== | ==Overall Reaction== | ||
[[Image:Reaction.PNG|350px|thumb|Overall reaction representing the hydrolysis of 2-AG by MGL]] | [[Image:Reaction.PNG|350px|thumb|Overall reaction representing the hydrolysis of 2-AG by MGL]] | ||