7S49
Crystal Structure of Inhibitor-bound Galactokinase
Summary for 7S49
| Entry DOI | 10.2210/pdb7s49/pdb |
| Related | 7RCL |
| Descriptor | Galactokinase, alpha-D-galactopyranose, (4R)-2-[(1,3-benzoxazol-2-yl)amino]-4-(4-chloro-1H-pyrazol-5-yl)-4,6,7,8-tetrahydroquinazolin-5(1H)-one, ... (6 entities in total) |
| Functional Keywords | galk, galactokinase, galactose, inhibitor, disulfide, sugar binding protein, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 85957.82 |
| Authors | Whitby, F.G. (deposition date: 2021-09-08, release date: 2021-09-29, Last modification date: 2024-10-30) |
| Primary citation | Liu, L.,Tang, M.,Pragani, R.,Whitby, F.G.,Zhang, Y.Q.,Balakrishnan, B.,Fang, Y.,Karavadhi, S.,Tao, D.,LeClair, C.A.,Hall, M.D.,Marugan, J.J.,Boxer, M.,Shen, M.,Hill, C.P.,Lai, K.,Patnaik, S. Structure-Based Optimization of Small Molecule Human Galactokinase Inhibitors. J.Med.Chem., 64:13551-13571, 2021 Cited by PubMed Abstract: Classic galactosemia is a rare disease caused by inherited deficiency of galactose-1 phosphate uridylyltransferase (GALT). Accumulation of galactose-1 phosphate (gal-1P) is thought to be the major cause of the chronic complications associated with this disease, which currently has no treatment. Inhibiting galactokinase (GALK1), the enzyme that generates galactose-1 phosphate, has been proposed as a novel strategy for treating classic galactosemia. Our previous work identified a highly selective unique dihydropyrimidine inhibitor against GALK1. With the determination of a co-crystal structure of this inhibitor with human GALK1, we initiated a structure-based structure-activity relationship (SAR) optimization campaign that yielded novel analogs with potent biochemical inhibition (IC < 100 nM). Lead compounds were also able to prevent gal-1P accumulation in patient-derived cells at low micromolar concentrations and have pharmacokinetic properties suitable for evaluation in rodent models of galactosemia. PubMed: 34491744DOI: 10.1021/acs.jmedchem.1c00945 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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