6pm9 | pdb_00006pm9

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

spinqualitylabelsall models 6pm9, resolution 2.86Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6pm9 is a 8 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: OQ1 Gene: MGEA5, HEXC, KIAA0679, MEA5 (HUMAN) Activity: Protein O-GlcNAcase, with EC number 3.2.1.169 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [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). 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. Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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