7RCM

Crystal Structure of ADP-bound Galactokinase

Summary for 7RCM

• Entry DOI: 10.2210/pdb7rcm/pdb
• Descriptor: Galactokinase, ADENOSINE-5'-DIPHOSPHATE, alpha-D-galactopyranose, ... (8 entities in total)
• Functional Keywords: galk, galactokinase, galactose, adp, disulfide, sugar binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 86377.26

Authors

Whitby, F.G. (deposition date: 2021-07-07, release date: 2021-09-29, Last modification date: 2024-10-09)

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

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: 34491744
DOI: 10.1021/acs.jmedchem.1c00945

Experimental method

X-RAY DIFFRACTION (2.1 Å)