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PDBsum entry 1ft2
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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
1ft2

 

 

 

 

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Contents
Protein chains
315 a.a. *
401 a.a. *
Ligands
FPP
Metals
_ZN
* Residue conservation analysis
PDB id:
1ft2
Name: Transferase
Title: Co-crystal structure of protein farnesyltransferase complexed with a farnesyl diphosphate substrate
Structure: Protein farnesyltransferase. Chain: a. Engineered: yes. Protein farnesyltransferase. Chain: b. Engineered: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Collection: atcc 63134 for alpha subunit, atcc 63127 for beta subunit. Organ: brain. Cellular_location: cytoplasm. Gene: cdna. Expressed in: spodoptera frugiperda.
Biol. unit: Dimer (from PDB file)
Resolution:
3.40Å     R-factor:   0.219     R-free:   0.268
Authors: L.S.Beese,P.J.Casey,S.B.Long
Key ref:
S.B.Long et al. (1998). Cocrystal structure of protein farnesyltransferase complexed with a farnesyl diphosphate substrate. Biochemistry, 37, 9612-9618. PubMed id: 9657673 DOI: 10.1021/bi980708e
Date:
02-Jun-98     Release date:   04-Nov-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q04631  (FNTA_RAT) -  Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha from Rattus norvegicus
Seq:
Struc: 		377 a.a.
315 a.a.
Protein chain
Pfam   ArchSchema ?
Q02293  (FNTB_RAT) -  Protein farnesyltransferase subunit beta from Rattus norvegicus
Seq:
Struc: 		437 a.a.
401 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 1: Chains A, B: E.C.2.5.1.58  - protein farnesyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: L-cysteinyl-[protein] + (2E,6E)-farnesyl diphosphate = S-(2E,6E)- farnesyl-L-cysteinyl-[protein] + diphosphate
L-cysteinyl-[protein]
Bound ligand (Het Group name = FPP)
corresponds exactly 		+ (2E,6E)-farnesyl diphosphate
 = S-(2E,6E)- farnesyl-L-cysteinyl-[protein]
 + diphosphate
      Cofactor: Mg(2+); Zn(2+)
   Enzyme class 2: Chain A: E.C.2.5.1.59  - protein geranylgeranyltransferase type I.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: geranylgeranyl diphosphate + L-cysteinyl-[protein] = S-geranylgeranyl-L- cysteinyl-[protein] + diphosphate
geranylgeranyl diphosphate
Bound ligand (Het Group name = FPP)
matches with 82.76% similarity 		+ L-cysteinyl-[protein]
 = S-geranylgeranyl-L- cysteinyl-[protein]
 + diphosphate
      Cofactor: Zn(2+)
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    
 
 
DOI no: 10.1021/bi980708e Biochemistry 37:9612-9618 (1998)
PubMed id: 9657673  
 
 
Cocrystal structure of protein farnesyltransferase complexed with a farnesyl diphosphate substrate.
S.B.Long, P.J.Casey, L.S.Beese.
 
  ABSTRACT  
 
Protein farnesyltransferase (FTase) catalyzes the transfer of the hydrophobic farnesyl group from farnesyl diphosphate (FPP) to cellular proteins such as Ras at a cysteine residue near their carboxy-terminus. This process is necessary for the subcellular localization of these proteins to the plasma membrane and is required for the transforming activity of oncogenic variants of Ras, making FTase a prime target for anticancer therapeutics. The high-resolution crystal structure of rat FTase was recently determined, and we present here the X-ray crystal structure of the first complex of FTase with a FPP substrate bound at the active site. The isoprenoid moiety of FPP binds in an extended conformation in a hydrophobic cavity of the beta subunit of the FTase enzyme, and the diphosphate moiety binds to a positively charged cleft at the top of this cavity near the subunit interface. The observed location of the FPP molecule is consistent with mutagenesis data. This binary complex of FTase with FPP leads us to suggest a "molecular ruler" hypothesis for isoprenoid substrate specificity, where the depth of the hydrophobic binding cavity acts as a ruler discriminating between isoprenoids of differing lengths. Although other length isoprenoids may bind in the cavity, only the 15-carbon farnesyl moiety binds with its C1 atom in register with a catalytic zinc ion as required for efficient transfer to the Ras substrate.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21212560 J.L.Li, P.Zhang, Y.M.Lee, J.Hong, E.S.Yoo, K.S.Bae, and J.H.Jung (2011).
Oxygenated Hexylitaconates from a marine sponge-derived fungus penicillium sp.
  Chem Pharm Bull (Tokyo), 59, 120-123.  
20565889 M.Andrews, D.H.Huizinga, and D.N.Crowell (2010).
The CaaX specificities of Arabidopsis protein prenyltransferases explain era1 and ggb phenotypes.
  BMC Plant Biol, 10, 118.  
19246009 M.A.Hast, S.Fletcher, C.G.Cummings, E.E.Pusateri, M.A.Blaskovich, K.Rivas, M.H.Gelb, W.C.Van Voorhis, S.M.Sebti, A.D.Hamilton, and L.S.Beese (2009).
Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase.
  Chem Biol, 16, 181-192.
PDB codes: 3e30 3e32 3e33 3e34 3e37
18648687 A.I.Anzellotti, and N.P.Farrell (2008).
Zinc metalloproteins as medicinal targets.
  Chem Soc Rev, 37, 1629-1651.  
18985644 T.Subramanian, S.Liu, J.M.Troutman, D.A.Andres, and H.P.Spielmann (2008).
Protein farnesyltransferase-catalyzed isoprenoid transfer to peptide depends on lipid size and shape, not hydrophobicity.
  Chembiochem, 9, 2872-2882.  
17918965 G.Cui, and K.M.Merz (2007).
Computational studies of the farnesyltransferase ternary complex part II: the conformational activation of farnesyldiphosphate.
  Biochemistry, 46, 12375-12381.  
17376731 J.Penner-Hahn (2007).
Zinc-promoted alkyl transfer: a new role for zinc.
  Curr Opin Chem Biol, 11, 166-171.  
17068802 S.F.Sousa, P.A.Fernandes, and M.J.Ramos (2007).
Theoretical studies on farnesyltransferase: the distances paradox explained.
  Proteins, 66, 205-218.  
17292915 W.Xie, C.Zhou, and R.H.Huang (2007).
Structure of tRNA dimethylallyltransferase: RNA modification through a channel.
  J Mol Biol, 367, 872-881.
PDB codes: 3crm 3crq 3crr
16527981 B.Li, J.P.Yu, J.S.Brunzelle, G.N.Moll, W.A.van der Donk, and S.K.Nair (2006).
Structure and mechanism of the lantibiotic cyclase involved in nisin biosynthesis.
  Science, 311, 1464-1467.
PDB codes: 2g02 2g0d
16892354 F.Minutolo, S.Bertini, L.Betti, R.Danesi, G.Gervasi, G.Giannaccini, A.Martinelli, A.M.Papini, E.Peroni, G.Placanica, S.Rapposelli, T.Tuccinardi, and M.Macchia (2006).
Synthesis of stable analogues of geranylgeranyl diphosphate possessing a (Z,E,E)-geranylgeranyl side chain, docking analysis, and biological assays for prenyl protein transferase inhibition.
  ChemMedChem, 1, 218-224.  
16554305 T.H.Chang, R.T.Guo, T.P.Ko, A.H.Wang, and P.H.Liang (2006).
Crystal structure of type-III geranylgeranyl pyrophosphate synthase from Saccharomyces cerevisiae and the mechanism of product chain length determination.
  J Biol Chem, 281, 14991-15000.
PDB code: 2dh4
16342942 G.Cui, B.Wang, and K.M.Merz (2005).
Computational studies of the farnesyltransferase ternary complex part I: substrate binding.
  Biochemistry, 44, 16513-16523.  
16291686 H.Y.Sun, T.P.Ko, C.J.Kuo, R.T.Guo, C.C.Chou, P.H.Liang, and A.H.Wang (2005).
Homodimeric hexaprenyl pyrophosphate synthase from the thermoacidophilic crenarchaeon Sulfolobus solfataricus displays asymmetric subunit structures.
  J Bacteriol, 187, 8137-8148.
PDB codes: 2azj 2azk 2azl
16191483 N.Ferri, R.Paoletti, and A.Corsini (2005).
Lipid-modified proteins as biomarkers for cardiovascular disease: a review.
  Biomarkers, 10, 219-237.  
15501930 S.F.Sousa, P.A.Fernandes, and M.J.Ramos (2005).
Farnesyltransferase--new insights into the zinc-coordination sphere paradigm: evidence for a carboxylate-shift mechanism.
  Biophys J, 88, 483-494.  
16607571 W.C.Guida, A.D.Hamilton, J.W.Crotty, and S.M.Sebti (2005).
Protein farnesyltransferase: flexible docking studies on inhibitors using computational modeling.
  J Comput Aided Mol Des, 19, 871-885.  
15044730 S.Y.Chang, T.P.Ko, A.P.Chen, A.H.Wang, and P.H.Liang (2004).
Substrate binding mode and reaction mechanism of undecaprenyl pyrophosphate synthase deduced from crystallographic studies.
  Protein Sci, 13, 971-978.
PDB code: 1v7u
15272304 V.E.Ahn, E.I.Lo, C.K.Engel, L.Chen, P.M.Hwang, L.E.Kay, R.E.Bishop, and G.G.Privé (2004).
A hydrocarbon ruler measures palmitate in the enzymatic acylation of endotoxin.
  EMBO J, 23, 2931-2941.
PDB code: 1thq
14532266 J.S.Pickett, K.E.Bowers, and C.A.Fierke (2003).
Mutagenesis studies of protein farnesyltransferase implicate aspartate beta 352 as a magnesium ligand.
  J Biol Chem, 278, 51243-51250.  
14609943 J.S.Taylor, T.S.Reid, K.L.Terry, P.J.Casey, and L.S.Beese (2003).
Structure of mammalian protein geranylgeranyltransferase type-I.
  EMBO J, 22, 5963-5974.
PDB codes: 1n4p 1n4q 1n4r 1n4s
12620235 O.Pylypenko, A.Rak, R.Reents, A.Niculae, V.Sidorovitch, M.D.Cioaca, E.Bessolitsyna, N.H.Thomä, H.Waldmann, I.Schlichting, R.S.Goody, and K.Alexandrov (2003).
Structure of Rab escort protein-1 in complex with Rab geranylgeranyltransferase.
  Mol Cell, 11, 483-494.
PDB code: 1ltx
11756461 C.C.Huang, C.V.Smith, M.S.Glickman, W.R.Jacobs, and J.C.Sacchettini (2002).
Crystal structures of mycolic acid cyclopropane synthases from Mycobacterium tuberculosis.
  J Biol Chem, 277, 11559-11569.
PDB codes: 1kp9 1kpg 1kph 1kpi 1l1e
12510823 K.N.Cho, and K.I.Lee (2002).
Chemistry and biology of Ras farnesyltransferase.
  Arch Pharm Res, 25, 759-769.  
12135472 P.H.Liang, T.P.Ko, and A.H.Wang (2002).
Structure, mechanism and function of prenyltransferases.
  Eur J Biochem, 269, 3339-3354.  
12374986 S.B.Long, P.J.Casey, and L.S.Beese (2002).
Reaction path of protein farnesyltransferase at atomic resolution.
  Nature, 419, 645-650.
PDB codes: 1kzo 1kzp 1kzr
11501754 H.C.Schmid, U.Oster, J.Kögel, S.Lenz, and W.Rüdiger (2001).
Cloning and characterisation of chlorophyll synthase from Avena sativa.
  Biol Chem, 382, 903-911.  
11170422 K.E.Hightower, P.J.Casey, and C.A.Fierke (2001).
Farnesylation of nonpeptidic thiol compounds by protein farnesyltransferase.
  Biochemistry, 40, 1002-1010.  
11687658 S.B.Long, P.J.Hancock, A.M.Kral, H.W.Hellinga, and L.S.Beese (2001).
The crystal structure of human protein farnesyltransferase reveals the basis for inhibition by CaaX tetrapeptides and their mimetics.
  Proc Natl Acad Sci U S A, 98, 12948-12953.
PDB codes: 1jcq 1jcr 1jcs
10704208 C.Huang, K.E.Hightower, and C.A.Fierke (2000).
Mechanistic studies of rat protein farnesyltransferase indicate an associative transition state.
  Biochemistry, 39, 2593-2602.  
11131164 D.M.Cermak, D.F.Wiemer, K.Lewis, and R.J.Hohl (2000).
2-(Acyloxy)ethylphosphonate analogues of prenyl pyrophosphates: synthesis and biological characterization.
  Bioorg Med Chem, 8, 2729-2737.  
10749864 F.S.Buckner, K.Yokoyama, L.Nguyen, A.Grewal, H.Erdjument-Bromage, P.Tempst, C.L.Strickland, L.Xiao, W.C.Van Voorhis, and M.H.Gelb (2000).
Cloning, heterologous expression, and distinct substrate specificity of protein farnesyltransferase from Trypanosoma brucei.
  J Biol Chem, 275, 21870-21876.  
11170866 G.C.Prendergast, and A.Oliff (2000).
Farnesyltransferase inhibitors: antineoplastic properties, mechanisms of action, and clinical prospects.
  Semin Cancer Biol, 10, 443-452.  
10745007 H.Zhang, M.C.Seabra, and J.Deisenhofer (2000).
Crystal structure of Rab geranylgeranyltransferase at 2.0 A resolution.
  Structure, 8, 241-251.
PDB code: 1dce
10785368 K.Sauer, and R.K.Thauer (2000).
Methyl-coenzyme M formation in methanogenic archaea. Involvement of zinc in coenzyme M activation.
  Eur J Biochem, 267, 2498-2504.  
11015220 M.J.Saderholm, K.E.Hightower, and C.A.Fierke (2000).
Role of metals in the reaction catalyzed by protein farnesyltransferase.
  Biochemistry, 39, 12398-12405.  
11076503 R.A.Spence, K.E.Hightower, K.L.Terry, L.S.Beese, C.A.Fierke, and P.J.Casey (2000).
Conversion of Tyr361 beta to Leu in mammalian protein farnesyltransferase impairs product release but not substrate recognition.
  Biochemistry, 39, 13651-13659.  
10673434 S.B.Long, P.J.Casey, and L.S.Beese (2000).
The basis for K-Ras4B binding specificity to protein farnesyltransferase revealed by 2 A resolution ternary complex structures.
  Structure, 8, 209-222.
PDB codes: 1d8d 1d8e
10732974 S.B.Singh, H.Jayasuriya, K.C.Silverman, C.A.Bonfiglio, J.M.Williamson, and R.B.Lingham (2000).
Efficient syntheses, human and yeast farnesyl-protein transferase inhibitory activities of chaetomellic acids and analogues.
  Bioorg Med Chem, 8, 571-580.  
10617635 W.Yang, J.Urano, and F.Tamanoi (2000).
Protein farnesylation is critical for maintaining normal cell morphology and canavanine resistance in Schizosaccharomyces pombe.
  J Biol Chem, 275, 429-438.  
  11106157 Y.P.Pang, K.Xu, J.E.Yazal, and F.G.Prendergas (2000).
Successful molecular dynamics simulation of the zinc-bound farnesyltransferase using the cationic dummy atom approach.
  Protein Sci, 9, 1857-1865.
PDB code: 1qe2
10382537 A.Oliff (1999).
Farnesyltransferase inhibitors: targeting the molecular basis of cancer.
  Biochim Biophys Acta, 1423, C19-C30.  
  10452610 H.Zhang, and N.V.Grishin (1999).
The alpha-subunit of protein prenyltransferases is a member of the tetratricopeptide repeat family.
  Protein Sci, 8, 1658-1667.  
10419854 J.K.Buolamwini (1999).
Novel anticancer drug discovery.
  Curr Opin Chem Biol, 3, 500-509.  
10480914 K.Del Villar, J.Urano, L.Guo, and F.Tamanoi (1999).
A mutant form of human protein farnesyltransferase exhibits increased resistance to farnesyltransferase inhibitors.
  J Biol Chem, 274, 27010-27017.  
10226042 K.E.Hightower, and C.A.Fierke (1999).
Zinc-catalyzed sulfur alkyation:insights from protein farnesyltransferase.
  Curr Opin Chem Biol, 3, 176-181.  
10542413 K.Wang, and S.Ohnuma (1999).
Chain-length determination mechanism of isoprenyl diphosphate synthases and implications for molecular evolution.
  Trends Biochem Sci, 24, 445-451.  
10651272 M.Scarsi, N.Majeux, and A.Caflisch (1999).
Hydrophobicity at the surface of proteins.
  Proteins, 37, 565-575.  
10625458 Z.S.Zhou, K.Peariso, J.E.Penner-Hahn, and R.G.Matthews (1999).
Identification of the zinc ligands in cobalamin-independent methionine synthase (MetE) from Escherichia coli.
  Biochemistry, 38, 15915-15926.  
9843427 C.L.Strickland, W.T.Windsor, R.Syto, L.Wang, R.Bond, Z.Wu, J.Schwartz, H.V.Le, L.S.Beese, and P.C.Weber (1998).
Crystal structure of farnesyl protein transferase complexed with a CaaX peptide and farnesyl diphosphate analogue.
  Biochemistry, 37, 16601-16611.
PDB code: 1qbq
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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