4DT2
Crystal structure of red kidney bean purple acid phosphatase in complex with Maybridge fragment CC27209
Summary for 4DT2
| Entry DOI | 10.2210/pdb4dt2/pdb |
| Related | 4DHL 4DSY |
| Descriptor | Purple acid phosphatase, 1,2-ETHANEDIOL, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (12 entities in total) |
| Functional Keywords | phosphatase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Phaseolus vulgaris (French bean,kidney bean,string bean) |
| Total number of polymer chains | 4 |
| Total formula weight | 207834.06 |
| Authors | Feder, D.,Hussein, W.M.,Clayton, D.J.,Kan, M.,Schenk, G.,McGeary, R.P.,Guddat, L.W. (deposition date: 2012-02-20, release date: 2012-09-19, Last modification date: 2024-11-06) |
| Primary citation | 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 Cited by 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: 22943065DOI: 10.1111/cbdd.12001 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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