2q58

Cryptosporidium parvum putative polyprenyl pyrophosphate synthase (cgd4_2550) in complex with zoledronate

spinqualitylabelsall models 2q58, resolution 2.37Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2q58 is a 2 chain structure with sequence from Cryptosporidium parvum Iowa II. This structure supersedes the now removed PDB entry 2her. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.37Å Ligands: MG, ZOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q5CR09_CRYPI 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 Cryptosporidiosis is a neglected disease without a wholly effective drug. We present a study demonstrating nitrogen-containing bisphosphonates (N-BPs) to be capable of inhibiting Cryptosporidium parvum at low micromolar concentrations in infected MDCK cells. Predictably, the mechanism of action is based on inhibition of biosynthesis of isoprenoids but the target enzyme is unexpectedly a distinctive C. parvum enzyme dubbed nonspecific polyprenyl pyrophosphate synthase (CpNPPPS). This enzyme produces various isoprenoid products larger than FPP and is inhibited by N-BPs at subnanomolar concentrations. It is part of an isoprenoid pathway in Cryptosporidium distinctly different from other organisms. The proposed mechanism of action is corroborated by crystal structures of the enzyme with risedronate and zoledronate bound showing how this enzyme's unique chain length determinant region enables it to accommodate larger substrates and products. These results, combined with existing data on their clinical use, demonstrate that N-BPs are very promising anticryptosporidial drug candidates. Targeting a uniquely nonspecific prenyl synthase with bisphosphonates to combat cryptosporidiosis.,Artz JD, Dunford JE, Arrowood MJ, Dong A, Chruszcz M, Kavanagh KL, Minor W, Russell RG, Ebetino FH, Oppermann U, Hui R Chem Biol. 2008 Dec 22;15(12):1296-306. PMID:19101474 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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