2f92

Crystal structure of human FPPS in complex with alendronate

spinqualitylabelsall models 2f92, resolution 2.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2f92 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: AHD, PO4, ZN Related: 2f7m, 2f89, 2f8c, 2f8z, 2f94, 2f9k Gene: FDPS, FPS, KIAA1293 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum Function [FPPS_HUMAN] Key enzyme in isoprenoid biosynthesis which catalyzes the formation of farnesyl diphosphate (FPP), a precursor for several classes of essential metabolites including sterols, dolichols, carotenoids, and ubiquinones. FPP also serves as substrate for protein farnesylation and geranylgeranylation. Catalyzes the sequential condensation of isopentenyl pyrophosphate with the allylic pyrophosphates, dimethylallyl pyrophosphate, and then with the resultant geranylpyrophosphate to the ultimate product farnesyl pyrophosphate. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed To understand the structural basis for bisphosphonate therapy of bone diseases, we solved the crystal structures of human farnesyl pyrophosphate synthase (FPPS) in its unliganded state, in complex with the nitrogen-containing bisphosphonate (N-BP) drugs zoledronate, pamidronate, alendronate, and ibandronate, and in the ternary complex with zoledronate and the substrate isopentenyl pyrophosphate (IPP). By revealing three structural snapshots of the enzyme catalytic cycle, each associated with a distinct conformational state, and details about the interactions with N-BPs, these structures provide a novel understanding of the mechanism of FPPS catalysis and inhibition. In particular, the accumulating substrate, IPP, was found to bind to and stabilize the FPPS-N-BP complexes rather than to compete with and displace the N-BP inhibitor. Stabilization of the FPPS-N-BP complex through IPP binding is supported by differential scanning calorimetry analyses of a set of representative N-BPs. Among other factors such as high binding affinity for bone mineral, this particular mode of FPPS inhibition contributes to the exceptional in vivo efficacy of N-BP drugs. Moreover, our data form the basis for structure-guided design of optimized N-BPs with improved pharmacological properties. Structural basis for the exceptional in vivo efficacy of bisphosphonate drugs.,Rondeau JM, Bitsch F, Bourgier E, Geiser M, Hemmig R, Kroemer M, Lehmann S, Ramage P, Rieffel S, Strauss A, Green JR, Jahnke W ChemMedChem. 2006 Feb;1(2):267-73. PMID:16892359 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Farnesyl diphosphate synthase

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