6OFD
The crystal structure of octadecyloxy(naphthalen-1-yl)methylphosphonic acid in complex with red kidney bean purple acid phosphatase
Summary for 6OFD
| Entry DOI | 10.2210/pdb6ofd/pdb |
| Descriptor | Fe(3+)-Zn(2+) purple acid phosphatase, [(S)-(naphthalen-1-yl)(octadecyloxy)methyl]phosphonic acid, SODIUM ION, ... (17 entities in total) |
| Functional Keywords | purple acid phosphatase, metallohydrolases, transition state, catalysis, osteoporosis, metal binding protein |
| Biological source | Phaseolus vulgaris (Kidney bean) |
| Total number of polymer chains | 4 |
| Total formula weight | 223835.76 |
| Authors | Feder, D.,Schenk, G.,Guddat, L.W.,Hussein, W.M.,McGeary, R.P.,Kan, M.W. (deposition date: 2019-03-29, release date: 2019-09-04, Last modification date: 2023-10-11) |
| Primary citation | Feder, D.,Kan, M.W.,Hussein, W.M.,Guddat, L.W.,Schenk, G.,McGeary, R.P. Synthesis, evaluation and structural investigations of potent purple acid phosphatase inhibitors as drug leads for osteoporosis. Eur.J.Med.Chem., 182:111611-111611, 2019 Cited by PubMed Abstract: Purple acid phosphatases (PAPs) are binuclear hydrolases that catalyze the hydrolysis of phosphorylated substrates under acidic to neutral conditions. Elevated serum concentrations of PAP are observed in patients suffering from osteoporosis, identifying this enzyme as a potential target for the development of novel therapeutic agents to treat this disease. α-Alkoxy-substituted naphthylmethylphosphonic acid derivatives have been identified previously as molecules that bind with high affinity to PAPs, and docking studies suggest that longer alkyl chains may increase the binding affinities of such compounds. Here, we synthesized several derivatives and tested their inhibitory effect against pig and red kidney bean PAPs. The most potent inhibitor within this series is the octadecyl derivative, which has a K value of ∼200 nM. Crystal structures of the dodecyl and octadecyl derivatives bound to red kidney bean PAP show that the length of the alkyl chain influences the ability of the phosphonate group to interact directly with the bimetallic center. These structures represent the first examples of potent inhibitors bound to a PAP that have drug-like properties. This study provides a starting point for the development of much needed new treatments for osteoporosis. PubMed: 31445230DOI: 10.1016/j.ejmech.2019.111611 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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