Useful Information
Human farnesyl diphosphate synthase in complex with NE58025
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PDB Code 3CP6 Target Class Miscellaneous Target FDPS + NE58025 Alias FDPS, FPS Disease Area/Function metabolism, signalling Date Deposited Mar 31 2008 Authors Related Structure 1YV5, 1ZW5, 2QIS, 3B7L
About this structure
A key branch point enzyme of the mevalonate pathway is farnesyl diphosphate synthase (FDPS, FPPS, EC 2.5.1.10 ), a Mg2+-dependent homodimeric enzyme, localized in peroxisomes. FDPS catalyzes the formation of both geranyl and farnesylpyrophosphate from isopentenyl pyrophosphate and dimethylallyl pyrophosphate. Post-translational modification of C-terminal CAAX sequences by covalent attachment of these isoprenyl chains is crucial for intracellular localization and proper function of small GTPases such as Ras, Rac, Rho , and CDC42.Nitrogen-containing bisphosphonates (N-BPs) are known inhibitors of farnesyl diphosphate synthase and are currently used to treat osteoporosis, Paget’s disease of the bone, and malignant bone tumours. Bisphosphonate therapy, which inhibits bone resorption, reduces the risk of fracture by 50% within one year. NE58025 is a research compound with 2 isomers. The 1R6S isomer projects the ring nitrogen towards the Lys200/Thr201 motif of the wildtype FPPS and is a potent inhibitor of FPPS, whereas its sister compound, the 1S6R isomer, projects the ring nitrogen away from the Lys200/Thr201 and is a poor inhibitor. An understanding of the mode of binding of NE58025 1R6S to an FDPS mutant that (Thr201Ala) adds to our understanding of the mechanism of inhibition of this important drug target.
