2O1O
Cryptosporidium parvum putative polyprenyl pyrophosphate synthase (cgd4_2550) in complex with risedronate.
Summary for 2O1O
| Entry DOI | 10.2210/pdb2o1o/pdb |
| Related | 2HER |
| Descriptor | Putative farnesyl pyrophosphate synthase, MAGNESIUM ION, 1-HYDROXY-2-(3-PYRIDINYL)ETHYLIDENE BIS-PHOSPHONIC ACID, ... (4 entities in total) |
| Functional Keywords | putative polyprenyl pyrophosphate synthase, structural genomics, structural genomics consortium, sgc, unknown function |
| Biological source | Cryptosporidium parvum |
| Total number of polymer chains | 2 |
| Total formula weight | 86658.16 |
| Authors | Chruszcz, M.,Artz, J.D.,Dong, A.,Dunford, J.,Lew, J.,Zhao, Y.,Kozieradski, I.,Kavanaugh, K.L.,Oppermann, U.,Sundstrom, M.,Weigelt, J.,Edwards, A.M.,Arrowsmith, C.H.,Bochkarev, A.,Hui, R.,Minor, W.,Structural Genomics Consortium (SGC) (deposition date: 2006-11-29, release date: 2006-12-12, Last modification date: 2023-08-30) |
| Primary citation | Artz, J.D.,Dunford, J.E.,Arrowood, M.J.,Dong, A.,Chruszcz, M.,Kavanagh, K.L.,Minor, W.,Russell, R.G.,Ebetino, F.H.,Oppermann, U.,Hui, R. Targeting a uniquely nonspecific prenyl synthase with bisphosphonates to combat cryptosporidiosis Chem.Biol., 15:1296-1306, 2008 Cited by PubMed Abstract: 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. PubMed: 19101474DOI: 10.1016/j.chembiol.2008.10.017 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.42 Å) |
Structure validation
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