6pm9

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<StructureSection load='6pm9' size='340' side='right'caption='[[6pm9]], [[Resolution|resolution]] 2.86&Aring;' scene=''>
<StructureSection load='6pm9' size='340' side='right'caption='[[6pm9]], [[Resolution|resolution]] 2.86&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6pm9]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PM9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PM9 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6pm9]] is a 8 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=6PM9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PM9 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=OQ1:(3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol'>OQ1</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.86&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MGEA5, HEXC, KIAA0679, MEA5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OQ1:(3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol'>OQ1</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein_O-GlcNAcase Protein O-GlcNAcase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.169 3.2.1.169] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6pm9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pm9 OCA], [https://pdbe.org/6pm9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pm9 RCSB], [https://www.ebi.ac.uk/pdbsum/6pm9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pm9 ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6pm9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pm9 OCA], [http://pdbe.org/6pm9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pm9 RCSB], [http://www.ebi.ac.uk/pdbsum/6pm9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pm9 ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/OGA_HUMAN OGA_HUMAN]] Isoform 1: Cleaves GlcNAc but not GalNAc from O-glycosylated proteins. Can use p-nitrophenyl-beta-GlcNAc and 4-methylumbelliferone-GlcNAc as substrates but not p-nitrophenyl-beta-GalNAc or p-nitrophenyl-alpha-GlcNAc (in vitro) (PubMed:11148210). Does not bind acetyl-CoA and does not have histone acetyltransferase activity (PubMed:24088714).<ref>PMID:11148210</ref> <ref>PMID:11788610</ref> <ref>PMID:20673219</ref> <ref>PMID:22365600</ref> <ref>PMID:24088714</ref> Isoform 3: Cleaves GlcNAc but not GalNAc from O-glycosylated proteins. Can use p-nitrophenyl-beta-GlcNAc as substrate but not p-nitrophenyl-beta-GalNAc or p-nitrophenyl-alpha-GlcNAc (in vitro), but has about six times lower specific activity than isoform 1.<ref>PMID:20673219</ref>
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[https://www.uniprot.org/uniprot/OGA_HUMAN OGA_HUMAN] Isoform 1: Cleaves GlcNAc but not GalNAc from O-glycosylated proteins. Can use p-nitrophenyl-beta-GlcNAc and 4-methylumbelliferone-GlcNAc as substrates but not p-nitrophenyl-beta-GalNAc or p-nitrophenyl-alpha-GlcNAc (in vitro) (PubMed:11148210). Does not bind acetyl-CoA and does not have histone acetyltransferase activity (PubMed:24088714).<ref>PMID:11148210</ref> <ref>PMID:11788610</ref> <ref>PMID:20673219</ref> <ref>PMID:22365600</ref> <ref>PMID:24088714</ref> Isoform 3: Cleaves GlcNAc but not GalNAc from O-glycosylated proteins. Can use p-nitrophenyl-beta-GlcNAc as substrate but not p-nitrophenyl-beta-GalNAc or p-nitrophenyl-alpha-GlcNAc (in vitro), but has about six times lower specific activity than isoform 1.<ref>PMID:20673219</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) exposure, metabolic stability, favorable pharmacokinetics, and robust in vivo pharmacodynamic response. Herein, we describe the medicinal chemistry and pharmacological studies that led to the identification of (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5H-pyra no[3,2-d]thiazole-6,7-diol 42 (MK-8719), a highly potent and selective OGA inhibitor with excellent CNS penetration that has been advanced to first-in-human phase I clinical trials.
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Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies.,Selnick HG, Hess JF, Tang C, Liu K, Schachter JB, Ballard JE, Marcus J, Klein DJ, Wang X, Pearson M, Savage MJ, Kaul R, Li TS, Vocadlo DJ, Zhou Y, Zhu Y, Mu C, Wang Y, Wei Z, Bai C, Duffy JL, McEachern EJ J Med Chem. 2019 Nov 27;62(22):10062-10097. doi: 10.1021/acs.jmedchem.9b01090., Epub 2019 Sep 29. PMID:31487175<ref>PMID:31487175</ref>
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==See Also==
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*[[O-GlcNAcase|O-GlcNAcase]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6pm9" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Protein O-GlcNAcase]]
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[[Category: Duffy JL]]
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[[Category: Duffy, J L]]
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[[Category: Klein DJ]]
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[[Category: Klein, D J]]
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[[Category: McEachern EJ]]
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[[Category: McEachern, E J]]
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[[Category: Selnick HG]]
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[[Category: Selnick, H G]]
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[[Category: Gh84]]
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[[Category: Hydrolase]]
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[[Category: Inhibitor]]
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[[Category: O-glcnacase]]
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Current revision

Crystal structure of the core catalytic domain of human O-GlcNAcase bound to MK-8719

PDB ID 6pm9

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

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