7S4C

Crystal Structure of Inhibitor-bound Galactokinase

7S4C の概要

• エントリーDOI: 10.2210/pdb7s4c/pdb
• 関連するPDBエントリー: 7RCL 7RCM 7S49
• 分子名称: Galactokinase, alpha-D-galactopyranose, 2-({(4R)-4-(2-chlorophenyl)-2-[(6-fluoro-1,3-benzoxazol-2-yl)amino]-6-methyl-1,4-dihydropyrimidine-5-carbonyl}amino)pyridine-4-carboxylic acid, ... (6 entities in total)
• 機能のキーワード: galk, galactokinase, galactose, inhibitor, disulfide, sugar binding protein, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 86754.92

構造登録者

Whitby, F.G. (登録日: 2021-09-08, 公開日: 2021-09-29, 最終更新日: 2024-10-16)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.2 Å)