4DSY

Crystal structure of red kidney bean purple acid phosphatase in complex with Maybridge fragment CC24201

4DSY の概要

• エントリーDOI: 10.2210/pdb4dsy/pdb
• 関連するPDBエントリー: 4DHL
• 分子名称: Purple acid phosphatase, 1,2-ETHANEDIOL, ACETATE ION, ... (12 entities in total)
• 機能のキーワード: phosphatase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Phaseolus vulgaris (French bean,kidney bean,string bean)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 207809.08

構造登録者

Feder, D.,Hussein, W.M.,Clayton, D.J.,Kan, M.,Schenk, G.,McGeary, R.P.,Guddat, L.W. (登録日: 2012-02-20, 公開日: 2012-09-19, 最終更新日: 2024-11-06)

主引用文献

Feder, D.,Hussein, W.M.,Clayton, D.J.,Kan, M.W.,Schenk, G.,McGeary, R.P.,Guddat, L.W.
Identification of purple acid phosphatase inhibitors by fragment-based screening: promising new leads for osteoporosis therapeutics.
Chem.Biol.Drug Des., 80:665-674, 2012

PubMed Abstract: Purple acid phosphatases are metalloenzymes found in animals, plants and fungi. They possess a binuclear metal centre to catalyse the hydrolysis of phosphate esters and anhydrides under acidic conditions. In humans, elevated purple acid phosphatases levels in sera are correlated with the progression of osteoporosis and metabolic bone malignancies, making this enzyme a target for the development of new chemotherapeutics to treat bone-related illnesses. To date, little progress has been achieved towards the design of specific and potent inhibitors of this enzyme that have drug-like properties. Here, we have undertaken a fragment-based screening approach using a 500-compound library identifying three inhibitors of purple acid phosphatases with K(i) values in the 30-60 μm range. Ligand efficiency values are 0.39-0.44 kcal/mol per heavy atom. X-ray crystal structures of these compounds in complex with a plant purple acid phosphatases (2.3-2.7 Å resolution) have been determined and show that all bind in the active site within contact of the binuclear centre. For one of these compounds, the phenyl ring is positioned within 3.5 Å of the binuclear centre. Docking simulations indicate that the three compounds fit into the active site of human purple acid phosphatases. These studies open the way to the design of more potent and selective inhibitors of purple acid phosphatases that can be tested as anti-osteoporotic drug leads.

PubMed: 22943065
DOI: 10.1111/cbdd.12001

実験手法

X-RAY DIFFRACTION (2.3 Å)