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2EWG

T. brucei Farnesyl Diphosphate Synthase Complexed with Minodronate

Summary for 2EWG
Entry DOI10.2210/pdb2ewg/pdb
Descriptorfarnesyl pyrophosphate synthase, MAGNESIUM ION, (1-HYDROXY-2-IMIDAZO[1,2-A]PYRIDIN-3-YLETHANE-1,1-DIYL)BIS(PHOSPHONIC ACID), ... (5 entities in total)
Functional Keywordsprotein-bisphosphonate complex, transferase
Biological sourceTrypanosoma brucei
Total number of polymer chains2
Total formula weight89969.88
Authors
Cao, R.,Mao, J.,Gao, Y.,Robinson, H.,Odeh, S.,Goddard, A.,Oldfield, E. (deposition date: 2005-11-03, release date: 2006-10-31, Last modification date: 2024-02-14)
Primary citationMao, J.,Mukherjee, S.,Zhang, Y.,Cao, R.,Sanders, J.M.,Song, Y.,Zhang, Y.,Meints, G.A.,Gao, Y.G.,Mukkamala, D.,Hudock, M.P.,Oldfield, E.
Solid-state NMR, crystallographic, and computational investigation of bisphosphonates and farnesyl diphosphate synthase-bisphosphonate complexes.
J.Am.Chem.Soc., 128:14485-14497, 2006
Cited by
PubMed Abstract: Bisphosphonates are a class of molecules in widespread use in treating bone resorption diseases and are also of interest as immunomodulators and anti-infectives. They function by inhibiting the enzyme farnesyl diphosphate synthase (FPPS), but the details of how these molecules bind are not fully understood. Here, we report the results of a solid-state (13)C, (15)N, and (31)P magic-angle sample spinning (MAS) NMR and quantum chemical investigation of several bisphosphonates, both as pure compounds and when bound to FPPS, to provide information about side-chain and phosphonate backbone protonation states when bound to the enzyme. We then used computational docking methods (with the charges assigned by NMR) to predict how several bisphosphonates bind to FPPS. Finally, we used X-ray crystallography to determine the structures of two potent bisphosphonate inhibitors, finding good agreement with the computational results, opening up the possibility of using the combination of NMR, quantum chemistry and molecular docking to facilitate the design of other, novel prenytransferase inhibitors.
PubMed: 17090032
DOI: 10.1021/ja061737c
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.48 Å)
Structure validation

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