4k10 | pdb_00004k10

Crystal Structure of Leshmaniasis major Farnesyl diphosphate synthase in complex with 3-FLUORO-1-(2-HYDROXY-2,2-DIPHOSPHONOETHYL)PYRIDINIUM and Mg2+

spinqualitylabelsall models 4k10, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4k10 is a 4 chain structure with sequence from Leima. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT, MES, MG, NA, NI9, PEG Related: 4jzb, 4jzx Gene: FPPS, LMJF_22_1360 (LEIMA) Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed Farnesyl diphosphate synthase (FPPS) is an essential enzyme involved in the biosynthesis of sterols (cholesterol in humans and ergosterol in yeasts, fungi and trypanosomatid parasites) as well as in protein prenylation. It is inhibited by bisphosphonates, a class of drugs used in humans to treat diverse bone-related diseases. The development of bisphosphonates as antiparasitic compounds targeting ergosterol biosynthesis has become an important route for therapeutic intervention. Here, the X-ray crystallographic structures of complexes of FPPS from Leishmania major (the causative agent of cutaneous leishmaniasis) with three bisphosphonates determined at resolutions of 1.8, 1.9 and 2.3 A are reported. Two of the inhibitors, 1-(2-hydroxy-2,2-diphosphonoethyl)-3-phenylpyridinium (300B) and 3-butyl-1-(2,2-diphosphonoethyl)pyridinium (476A), co-crystallize with the homoallylic substrate isopentenyl diphosphate (IPP) and three Ca(2+) ions. A third inhibitor, 3-fluoro-1-(2-hydroxy-2,2-diphosphonoethyl)pyridinium (46I), was found to bind two Mg(2+) ions but not IPP. Calorimetric studies showed that binding of the inhibitors is entropically driven. Comparison of the structures of L. major FPPS (LmFPPS) and human FPPS provides new information for the design of bisphosphonates that will be more specific for inhibition of LmFPPS. The asymmetric structure of the LmFPPS-46I homodimer indicates that binding of the allylic substrate to both monomers of the dimer results in an asymmetric dimer with one open and one closed homoallylic site. It is proposed that IPP first binds to the open site, which then closes, opening the site on the other monomer, which closes after binding the second IPP, leading to the symmetric fully occupied FPPS dimer observed in other structures. Structural and thermodynamic basis of the inhibition of Leishmania major farnesyl diphosphate synthase by nitrogen-containing bisphosphonates.,Aripirala S, Gonzalez-Pacanowska D, Oldfield E, Kaiser M, Amzel LM, Gabelli SB Acta Crystallogr D Biol Crystallogr. 2014 Mar;70(Pt 3):802-10. doi:, 10.1107/S1399004713033221. Epub 2014 Feb 22. PMID:24598749 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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