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PDBsum entry 3dyh
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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
3dyh

 

 

 

 

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Contents
Protein chains
358 a.a. *
Ligands
721 ×2
Metals
_MG ×6
Waters ×349
* Residue conservation analysis
PDB id:
3dyh
Name: Transferase
Title: T. Brucei farnesyl diphosphate synthase complexed with bisphosphonate bph-721
Structure: Farnesyl pyrophosphate synthase. Chain: a, b. Engineered: yes
Source: Trypanosoma brucei. Organism_taxid: 5691. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
1.94Å     R-factor:   0.242     R-free:   0.282
Authors: R.Cao,Y.Gao,H.Robinson,A.Goddard,E.Oldfield
Key ref: Y.Zhang et al. (2009). Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation. J Am Chem Soc, 131, 5153-5162. PubMed id: 19309137
Date:
27-Jul-08     Release date:   05-May-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q86C09  (Q86C09_9TRYP) -  Farnesyl pyrophosphate synthase (Fragment) from Trypanosoma brucei
Seq:
Struc: 		367 a.a.
358 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.5.1.10  - (2E,6E)-farnesyl diphosphate synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway: 		Terpenoid biosynthesis
      Reaction: isopentenyl diphosphate + (2E)-geranyl diphosphate = (2E,6E)-farnesyl diphosphate + diphosphate
isopentenyl diphosphate
 + (2E)-geranyl diphosphate
 = (2E,6E)-farnesyl diphosphate
 + diphosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
J Am Chem Soc 131:5153-5162 (2009)
PubMed id: 19309137  
 
 
Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation.
Y.Zhang, R.Cao, F.Yin, M.P.Hudock, R.T.Guo, K.Krysiak, S.Mukherjee, Y.G.Gao, H.Robinson, Y.Song, J.H.No, K.Bergan, A.Leon, L.Cass, A.Goddard, T.K.Chang, F.Y.Lin, E.Van Beek, S.Papapoulos, A.H.Wang, T.Kubo, M.Ochi, D.Mukkamala, E.Oldfield.
 
  ABSTRACT  
 
Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21076734 P.Canepa, F.Chiatti, M.Corno, Y.Sakhno, G.Martra, and P.Ugliengo (2011).
Affinity of hydroxyapatite (001) and (010) surfaces to formic and alendronic acids: a quantum-mechanical and infrared study.
  Phys Chem Chem Phys, 13, 1099-1111.  
21157775 R.J.Falconer, and B.M.Collins (2011).
Survey of the year 2009: applications of isothermal titration calorimetry.
  J Mol Recognit, 24, 1.  
20457823 A.P.Singh, Y.Zhang, J.H.No, R.Docampo, V.Nussenzweig, and E.Oldfield (2010).
Lipophilic bisphosphonates are potent inhibitors of Plasmodium liver-stage growth.
  Antimicrob Agents Chemother, 54, 2987-2993.  
20467558 E.Maltezou, M.Stylianou, S.Roy, C.Drouza, and A.D.Keramidas (2010).
Synthesis, solution, and structural characterization of tetrahydrofuranyl-2,2-bisphosphonic acid disodium salt.
  Bioinorg Chem Appl, (), 563875.  
20560544 E.Oldfield (2010).
Targeting isoprenoid biosynthesis for drug discovery: bench to bedside.
  Acc Chem Res, 43, 1216-1226.  
20957624 J.D.Compain, P.Mialane, J.Marrot, F.Sécheresse, W.Zhu, E.Oldfield, and A.Dolbecq (2010).
Tetra- to dodecanuclear oxomolybdate complexes with functionalized bisphosphonate ligands: activity in killing tumor cells.
  Chemistry, 16, 13741-13748.  
20544107 J.Gao, X.Chu, Y.Qiu, L.Wu, Y.Qiao, J.Wu, and D.Li (2010).
Discovery of potent inhibitor for farnesyl pyrophosphate synthase in the mevalonate pathway.
  Chem Commun (Camb), 46, 5340-5342.  
20711197 W.Jahnke, J.M.Rondeau, S.Cotesta, A.Marzinzik, X.Pellé, M.Geiser, A.Strauss, M.Götte, F.Bitsch, R.Hemmig, C.Henry, S.Lehmann, J.F.Glickman, T.P.Roddy, S.J.Stout, and J.R.Green (2010).
Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery.
  Nat Chem Biol, 6, 660-666.
PDB codes: 3n1v 3n1w 3n3l 3n45 3n46 3n49 3n5h 3n5j 3n6k
20173096 W.Wang, K.Wang, Y.L.Liu, J.H.No, J.Li, M.J.Nilges, and E.Oldfield (2010).
Bioorganometallic mechanism of action, and inhibition, of IspH.
  Proc Natl Acad Sci U S A, 107, 4522-4527.  
  20039246 Y.Zhang, R.Cao, F.Yin, F.Y.Lin, H.Wang, K.Krysiak, J.H.No, D.Mukkamala, K.Houlihan, J.Li, C.T.Morita, and E.Oldfield (2010).
Lipophilic pyridinium bisphosphonates: potent gammadelta T cell stimulators.
  Angew Chem Int Ed Engl, 49, 1136-1138.  
19489581 S.Mukherjee, C.Huang, F.Guerra, K.Wang, and E.Oldfield (2009).
Thermodynamics of bisphosphonates binding to human bone: a two-site model.
  J Am Chem Soc, 131, 8374-8375.  
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.

 

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