7KHS
OgOGA IN COMPLEX WITH LIGAND 55
Summary for 7KHS
| Entry DOI | 10.2210/pdb7khs/pdb |
| Descriptor | Protein O-GlcNAcase, N-(5-{[(5S)-7-(5-methylimidazo[1,2-a]pyrimidin-7-yl)-2,7-diazaspiro[4.4]nonan-2-yl]methyl}-1,3-thiazol-2-yl)acetamide, CALCIUM ION, ... (5 entities in total) |
| Functional Keywords | glycoside hydrolase, inhibitor, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | Oceanicola granulosus |
| Total number of polymer chains | 4 |
| Total formula weight | 202759.21 |
| Authors | Shaffer, P.L. (deposition date: 2020-10-21, release date: 2020-12-02, Last modification date: 2024-04-03) |
| Primary citation | Martinez-Viturro, C.M.,Trabanco, A.A.,Royes, J.,Fernandez, E.,Tresadern, G.,Vega, J.A.,Del Cerro, A.,Delgado, F.,Garcia Molina, A.,Tovar, F.,Shaffer, P.,Ebneth, A.,Bretteville, A.,Mertens, L.,Somers, M.,Alonso, J.M.,Bartolome-Nebreda, J.M. Diazaspirononane Nonsaccharide Inhibitors of O-GlcNAcase (OGA) for the Treatment of Neurodegenerative Disorders. J.Med.Chem., 63:14017-14044, 2020 Cited by PubMed Abstract: O-GlcNAcylation is a post-translational modification of tau understood to lower the speed and yield of its aggregation, a pathological hallmark of Alzheimer's disease (AD). O-GlcNAcase (OGA) is the only enzyme that removes O-linked -acetyl-d-glucosamine (O-GlcNAc) from target proteins. Therefore, inhibition of OGA represents a potential approach for the treatment of AD by preserving the O-GlcNAcylated tau protein. Herein, we report the multifactorial optimization of high-throughput screening hit to a potent, metabolically stable, and orally bioavailable diazaspirononane OGA inhibitor (+)-. The human OGA X-ray crystal structure has been recently solved, but bacterial hydrolases are still widely used as structural homologues. For the first time, we reveal how a nonsaccharide series of inhibitors binds bacterial OGA and discuss the suitability of two different bacterial orthologues as surrogates for human OGA. These breakthroughs enabled structure-activity relationships to be understood and provided context and boundaries for the optimization of druglike properties. PubMed: 33197187DOI: 10.1021/acs.jmedchem.0c01479 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.78 Å) |
Structure validation
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