4ga3

Crystal Structure of Human Farnesyl Diphosphate Synthase in Complex with BPH-1260

spinqualitylabelsall models 4ga3, resolution 2.39Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ga3 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 4GA, MG, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. Publication Abstract from PubMed We synthesized 30 lipophilic bisphosphonates and tested them in malaria parasite killing (targeting parasite geranylgeranyl diphosphate synthase, GGPPS) as well in human gammadelta T cell activation (targeting human farnesyl diphosphate synthase, FPPS). Similar patterns of activity were seen in inhibiting human FPPS and Plasmodium GGPPS, with short to medium chain-length species having most activity. In cells, shorter chain-length species had low activity, due to poor membrane permeability, and longer chain length species were poor enzyme inhibitors. Optimal activity was thus seen with ~C10 side-chains, which have the best combination of enzyme inhibition and cell penetration. We also solved the crystal structure of one potent inhibitor, bound to FPPS. The results are of interest since they suggest the possibility of a combined chemo/immuno-therapeutic approach to anti-malarial development in which both direct parasite killing as well as gammadelta T cell activation can be achieved with a single compound. Chemo-Immunotherapeutic Anti-Malarials Targeting Isoprenoid Biosynthesis.,Zhang Y, Zhu W, Liu YL, Wang H, Wang K, Li K, No JH, Ayong L, Gulati A, Pang R, Freitas-Junior L, Morita CT, Old-Field E ACS Med Chem Lett. 2013 Apr 11;4(4):423-427. PMID:23610597 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Farnesyl diphosphate synthase 3D structures

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