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PDBsum entry 2f8c
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protein ligands metals links
Transferase PDB id
2f8c

 

 

 

 

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JSmol PyMol  
Contents
Protein chain
343 a.a. *
Ligands
PO4
ZOL
Metals
_MG ×3
Waters ×135
* Residue conservation analysis
PDB id:
2f8c
Name: Transferase
Title: Crystal structure of fpps in complex with zoledronate
Structure: Farnesyl diphosphate synthase. Chain: f. Fragment: residues 6-353. Synonym: fpp synthetase. Fps. Farnesyl pyrophosphate synthetase. Engineered: yes. Other_details: includes: dimethylallyltranstransferase. Geranyltranstransferase
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: fdps, fps, kiaa1293. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PDB file)
Resolution:
2.20Å     R-factor:   0.222     R-free:   0.268
Authors: J.-M.Rondeau,F.Bitsch,E.Bourgier,M.Geiser,R.Hemmig,M.Kroemer, S.Lehmann,P.Ramage,S.Rieffel,A.Strauss,J.R.Green,W.Jahnke
Key ref: J.M.Rondeau et al. (2006). Structural basis for the exceptional in vivo efficacy of bisphosphonate drugs. Chemmedchem, 1, 267-273. PubMed id: 16892359
Date:
02-Dec-05     Release date:   28-Feb-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P14324  (FPPS_HUMAN) -  Farnesyl pyrophosphate synthase from Homo sapiens
Seq:
Struc: 		419 a.a.
343 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 1: E.C.2.5.1.1  - dimethylallyltranstransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway: 		Terpenoid biosynthesis
      Reaction: isopentenyl diphosphate + dimethylallyl diphosphate = (2E)- geranyl diphosphate + diphosphate
isopentenyl diphosphate
 + dimethylallyl diphosphate
 = (2E)- geranyl diphosphate
 +
diphosphate
Bound ligand (Het Group name = PO4)
matches with 55.56% similarity
   Enzyme class 2: E.C.2.5.1.10  - (2E,6E)-farnesyl diphosphate synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
      Reaction: isopentenyl diphosphate + (2E)-geranyl diphosphate = (2E,6E)-farnesyl diphosphate + diphosphate
isopentenyl diphosphate
 + (2E)-geranyl diphosphate
 = (2E,6E)-farnesyl diphosphate
 +
diphosphate
Bound ligand (Het Group name = PO4)
matches with 55.56% similarity
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
Chemmedchem 1:267-273 (2006)
PubMed id: 16892359  
 
 
Structural basis for the exceptional in vivo efficacy of bisphosphonate drugs.
J.M.Rondeau, F.Bitsch, E.Bourgier, M.Geiser, R.Hemmig, M.Kroemer, S.Lehmann, P.Ramage, S.Rieffel, A.Strauss, J.R.Green, W.Jahnke.
 
  ABSTRACT  
 
To understand the structural basis for bisphosphonate therapy of bone diseases, we solved the crystal structures of human farnesyl pyrophosphate synthase (FPPS) in its unliganded state, in complex with the nitrogen-containing bisphosphonate (N-BP) drugs zoledronate, pamidronate, alendronate, and ibandronate, and in the ternary complex with zoledronate and the substrate isopentenyl pyrophosphate (IPP). By revealing three structural snapshots of the enzyme catalytic cycle, each associated with a distinct conformational state, and details about the interactions with N-BPs, these structures provide a novel understanding of the mechanism of FPPS catalysis and inhibition. In particular, the accumulating substrate, IPP, was found to bind to and stabilize the FPPS-N-BP complexes rather than to compete with and displace the N-BP inhibitor. Stabilization of the FPPS-N-BP complex through IPP binding is supported by differential scanning calorimetry analyses of a set of representative N-BPs. Among other factors such as high binding affinity for bone mineral, this particular mode of FPPS inhibition contributes to the exceptional in vivo efficacy of N-BP drugs. Moreover, our data form the basis for structure-guided design of optimized N-BPs with improved pharmacological properties.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21149961 F.Fanord, K.Fairbairn, H.Kim, A.Garces, V.Bhethanabotla, and V.K.Gupta (2011).
Bisphosphonate-modified gold nanoparticles: a useful vehicle to study the treatment of osteonecrosis of the femoral head.
  Nanotechnology, 22, 035102.  
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
21420384 J.Räikkönen, M.Taskinen, J.E.Dunford, H.Mönkkönen, S.Auriola, and J.Mönkkönen (2011).
Correlation between time-dependent inhibition of human farnesyl pyrophosphate synthase and blockade of mevalonate pathway by nitrogen-containing bisphosphonates in cultured cells.
  Biochem Biophys Res Commun, 407, 663-667.  
19876942 C.H.Huang, S.B.Gabelli, E.Oldfield, and L.M.Amzel (2010).
Binding of nitrogen-containing bisphosphonates (N-BPs) to the Trypanosoma cruzi farnesyl diphosphate synthase homodimer.
  Proteins, 78, 888-899.
PDB codes: 3iba 3ick 3icm 3icn 3icz 3id0
20104347 E.Matczak-Jon, T.Kowalik-Jankowska, K.Slepokura, P.Kafarski, and A.Rajewska (2010).
Specificity of the zinc(II), magnesium(II) and calcium(II) complexation by (pyridin-2-yl)aminomethane-1,1-diphosphonic acids and related 1,3-(thiazol-2-yl) and 1,3-(benzothiazol-2-yl) derivatives.
  Dalton Trans, 39, 1207-1221.  
21098670 F.Y.Lin, C.I.Liu, Y.L.Liu, Y.Zhang, K.Wang, W.Y.Jeng, T.P.Ko, R.Cao, A.H.Wang, and E.Oldfield (2010).
Mechanism of action and inhibition of dehydrosqualene synthase.
  Proc Natl Acad Sci U S A, 107, 21337-21342.
PDB codes: 3lgz 3npr 3nri
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.  
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
20209564 W.Jahnke, and C.Henry (2010).
An in vitro assay to measure targeted drug delivery to bone mineral.
  ChemMedChem, 5, 770-776.  
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
  20126511 I.Podgorski (2009).
Future of anticathepsin K drugs: dual therapy for skeletal disease and atherosclerosis?
  Future Med Chem, 1, 21-34.  
19744312 N.Bivi, M.Romanello, R.Harrison, I.Clarke, D.C.Hoyle, L.Moro, F.Ortolani, A.Bonetti, F.Quadrifoglio, G.Tell, and D.Delneri (2009).
Identification of secondary targets of N-containing bisphosphonates in mammalian cells via parallel competition analysis of the barcoded yeast deletion collection.
  Genome Biol, 10, R93.  
19309137 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, and E.Oldfield (2009).
Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation.
  J Am Chem Soc, 131, 5153-5162.
PDB codes: 2opm 2zeu 2zev 3dyf 3dyg 3dyh 3efq 3egt
18800762 C.K-M Chen, M.P.Hudock, Y.Zhang, R.T.Guo, R.Cao, J.H.No, P.H.Liang, T.P.Ko, T.H.Chang, S.C.Chang, Y.Song, J.Axelson, A.Kumar, A.H.Wang, and E.Oldfield (2008).
Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation.
  J Med Chem, 51, 5594-5607.
PDB codes: 2z4v 2z4w 2z4x 2z4y 2z4z 2z50 2z52 2z78 2z7i
19101474 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, and R.Hui (2008).
Targeting a uniquely nonspecific prenyl synthase with bisphosphonates to combat cryptosporidiosis.
  Chem Biol, 15, 1296-1306.
PDB codes: 2o1o 2q58
18214569 R.G.Russell, N.B.Watts, F.H.Ebetino, and M.J.Rogers (2008).
Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy.
  Osteoporos Int, 19, 733-759.  
17291279 C.T.Morita, C.Jin, G.Sarikonda, and H.Wang (2007).
Nonpeptide antigens, presentation mechanisms, and immunological memory of human Vgamma2Vdelta2 T cells: discriminating friend from foe through the recognition of prenyl pyrophosphate antigens.
  Immunol Rev, 215, 59-76.  
17850825 H.Mönkkönen, P.D.Ottewell, J.Kuokkanen, J.Mönkkönen, S.Auriola, and I.Holen (2007).
Zoledronic acid-induced IPP/ApppI production in vivo.
  Life Sci, 81, 1066-1070.  
17638323 H.M.Weiss, B.Wirz, A.Schweitzer, R.Amstutz, M.I.Rodriguez Perez, H.Andres, Y.Metz, J.Gardiner, and D.Seebach (2007).
ADME investigations of unnatural peptides: distribution of a 14C-labeled beta 3-octaarginine in rats.
  Chem Biodivers, 4, 1413-1437.  
17477829 J.F.Glickman, and A.Schmid (2007).
Farnesyl pyrophosphate synthase: real-time kinetics and inhibition by nitrogen-containing bisphosphonates in a scintillation assay.
  Assay Drug Dev Technol, 5, 205-214.  
17535895 R.T.Guo, R.Cao, P.H.Liang, T.P.Ko, T.H.Chang, M.P.Hudock, W.Y.Jeng, C.K.Chen, Y.Zhang, Y.Song, C.J.Kuo, F.Yin, E.Oldfield, and A.H.Wang (2007).
Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases.
  Proc Natl Acad Sci U S A, 104, 10022-10027.
PDB codes: 2e8t 2e8u 2e8v 2e8w 2e8x 2e90 2e91 2e92 2e93 2e94 2e95 2e98 2e99 2e9a 2e9c 2e9d
16684881 K.L.Kavanagh, K.Guo, J.E.Dunford, X.Wu, S.Knapp, F.H.Ebetino, M.J.Rogers, R.G.Russell, and U.Oppermann (2006).
The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs.
  Proc Natl Acad Sci U S A, 103, 7829-7834.
PDB codes: 1yv5 1zw5
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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