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PDBsum entry 2q58

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
2q58
Jmol
Contents
Protein chains
335 a.a. *
Ligands
ZOL ×2
Metals
_MG ×6
Waters ×29
* Residue conservation analysis
PDB id:
2q58
Name: Transferase
Title: Cryptosporidium parvum putative polyprenyl pyrophosphate syn (cgd4_2550) in complex with zoledronate
Structure: Farnesyl pyrophosphate synthase. Chain: a, b. Synonym: fragment. Engineered: yes
Source: Cryptosporidium parvum. Organism_taxid: 353152. Strain: iowa ii. Gene: cgd4_2550. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.37Å     R-factor:   0.216     R-free:   0.238
Authors: M.Chruszcz,J.Artz,H.Zheng,A.Dong,J.Dunford,J.Lew,Y.Zhao, I.Kozieradski,K.L.Kavanaugh,U.Opperman,M.Sundstrom,J.Weigel A.Edwards,C.Arrowsmith,A.Bochkarev,R.Hui,W.Minor,Structural Consortium (Sgc)
Key ref: J.D.Artz et al. (2008). Targeting a uniquely nonspecific prenyl synthase with bisphosphonates to combat cryptosporidiosis. Chem Biol, 15, 1296-1306. PubMed id: 19101474
Date:
31-May-07     Release date:   12-Jun-07    
Supersedes: 2her
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q5CR09  (Q5CR09_CRYPI) -  Putative farnesyl pyrophosphate synthase (Fragment)
Seq:
Struc:
384 a.a.
335 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     isoprenoid biosynthetic process   1 term 
  Biochemical function     transferase activity     1 term  

 

 
Chem Biol 15:1296-1306 (2008)
PubMed id: 19101474  
 
 
Targeting a uniquely nonspecific prenyl synthase with bisphosphonates to combat cryptosporidiosis.
J.D.Artz, J.E.Dunford, M.J.Arrowood, A.Dong, M.Chruszcz, K.L.Kavanagh, W.Minor, R.G.Russell, F.H.Ebetino, U.Oppermann, R.Hui.
 
  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.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21084289 J.D.Artz, A.K.Wernimont, J.E.Dunford, M.Schapira, A.Dong, Y.Zhao, J.Lew, R.G.Russell, F.H.Ebetino, U.Oppermann, and R.Hui (2011).
Molecular characterization of a novel geranylgeranyl pyrophosphate synthase from Plasmodium parasites.
  J Biol Chem, 286, 3315-3322.
PDB codes: 3ldw 3mav 3ph7
20810277 M.Chruszcz, M.Domagalski, T.Osinski, A.Wlodawer, and W.Minor (2010).
Unmet challenges of structural genomics.
  Curr Opin Struct Biol, 20, 587-597.  
20689422 M.M.Cabada, and A.C.White (2010).
Treatment of cryptosporidiosis: do we know what we think we know?
  Curr Opin Infect Dis, 23, 494-499.  
20139160 T.H.Chang, F.L.Hsieh, T.P.Ko, K.H.Teng, P.H.Liang, and A.H.Wang (2010).
Structure of a heterotetrameric geranyl pyrophosphate synthase from mint (Mentha piperita) reveals intersubunit regulation.
  Plant Cell, 22, 454-467.
PDB codes: 3kra 3krc 3krf 3kro 3krp
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.