6ax1

From Proteopedia

(Difference between revisions)

Current revision

Structure of human monoacylglycerol lipase bound to a covalent inhibitor

Structural highlights

6ax1 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.26Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MGLL_HUMAN Converts monoacylglycerides to free fatty acids and glycerol. Hydrolyzes the endocannabinoid 2-arachidonoylglycerol, and thereby contributes to the regulation of endocannabinoid signaling, nociperception and perception of pain (By similarity). Regulates the levels of fatty acids that serve as signaling molecules and promote cancer cell migration, invasion and tumor growth.^[1]

Publication Abstract from PubMed

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.

Azetidine and Piperidine Carbamates as Efficient, Covalent Inhibitors of Monoacylglycerol Lipase.,Butler CR, Beck EM, Harris A, Huang Z, McAllister LA, Am Ende CW, Fennell K, Foley TL, Fonseca K, Hawrylik SJ, Johnson DS, Knafels JD, Mente S, Noell GS, Pandit J, Phillips TB, Piro JR, Rogers BN, Samad TA, Wang J, Wan S, Brodney MA J Med Chem. 2017 Dec 14;60(23):9860-9873. doi: 10.1021/acs.jmedchem.7b01531. Epub, 2017 Dec 5. PMID:29148769^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell. 2010 Jan 8;140(1):49-61. doi: 10.1016/j.cell.2009.11.027. PMID:20079333 doi:10.1016/j.cell.2009.11.027
↑ Butler CR, Beck EM, Harris A, Huang Z, McAllister LA, Am Ende CW, Fennell K, Foley TL, Fonseca K, Hawrylik SJ, Johnson DS, Knafels JD, Mente S, Noell GS, Pandit J, Phillips TB, Piro JR, Rogers BN, Samad TA, Wang J, Wan S, Brodney MA. Azetidine and Piperidine Carbamates as Efficient, Covalent Inhibitors of Monoacylglycerol Lipase. J Med Chem. 2017 Dec 14;60(23):9860-9873. doi: 10.1021/acs.jmedchem.7b01531. Epub, 2017 Dec 5. PMID:29148769 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01531

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6ax1"

Categories: Homo sapiens | Large Structures | Pandit J

@@ Line 3: / Line 3: @@
 <StructureSection load='6ax1' size='340' side='right'caption='[[6ax1]], [[Resolution|resolution]] 2.26&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ax1]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AX1 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6AX1 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ax1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AX1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6AX1 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C0S:1,1,1,3,3,3-hexafluoropropan-2-yl+3-(3-phenyl-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate'>C0S</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.26&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Acylglycerol_lipase Acylglycerol lipase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.23 3.1.1.23] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C0S:1,1,1,3,3,3-hexafluoropropan-2-yl+3-(3-phenyl-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate'>C0S</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6ax1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ax1 OCA], [http://pdbe.org/6ax1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ax1 RCSB], [http://www.ebi.ac.uk/pdbsum/6ax1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ax1 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6ax1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ax1 OCA], [https://pdbe.org/6ax1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ax1 RCSB], [https://www.ebi.ac.uk/pdbsum/6ax1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ax1 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/MGLL_HUMAN MGLL_HUMAN]] Converts monoacylglycerides to free fatty acids and glycerol. Hydrolyzes the endocannabinoid 2-arachidonoylglycerol, and thereby contributes to the regulation of endocannabinoid signaling, nociperception and perception of pain (By similarity). Regulates the levels of fatty acids that serve as signaling molecules and promote cancer cell migration, invasion and tumor growth.<ref>PMID:20079333</ref>
+[https://www.uniprot.org/uniprot/MGLL_HUMAN MGLL_HUMAN] Converts monoacylglycerides to free fatty acids and glycerol. Hydrolyzes the endocannabinoid 2-arachidonoylglycerol, and thereby contributes to the regulation of endocannabinoid signaling, nociperception and perception of pain (By similarity). Regulates the levels of fatty acids that serve as signaling molecules and promote cancer cell migration, invasion and tumor growth.<ref>PMID:20079333</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Acylglycerol lipase]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Pandit, J]]
+[[Category: Pandit J]]
-[[Category: Covalent inhibitor]]
-[[Category: Hydrolase]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]
-[[Category: Monoacylglycerol lipase]]
-[[Category: Sbdd]]

6ax1

From Proteopedia

Current revision

Structure of human monoacylglycerol lipase bound to a covalent inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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