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PDBsum entry 1jcs
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protein ligands metals Protein-protein interface(s) links
Transferase/transferase inhibitor PDB id
1jcs

 

 

 

 

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Contents
Protein chains
323 a.a. *
407 a.a. *
Ligands
THR-LYS-CYS-VAL-
PHE-MET
FII
ACY ×2
Metals
_ZN
Waters ×436
* Residue conservation analysis
PDB id:
1jcs
Name: Transferase/transferase inhibitor
Title: Crystal structure of rat protein farnesyltransferase complexed with the peptide substrate tkcvfm and an analog of farnesyl diphosphate
Structure: Protein farnesyltransferase, alpha subunit. Chain: a. Fragment: alpha subunit. Synonym: caax farnesyltransferase alpha subunit. Ras proteins prenyltransferase alpha. Ftase-alpha. Prenyl-protein transferase ram2 homolog. Engineered: yes. Protein farnesyltransferase, beta subunit. Chain: b.
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_atcc_number: 63134. Synthetic: yes
Biol. unit: Trimer (from PQS)
Resolution:
2.20Å     R-factor:   0.160     R-free:   0.202
Authors: S.B.Long,P.J.Casey,L.S.Beese
Key ref:
S.B.Long et al. (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. PubMed id: 11687658 DOI: 10.1073/pnas.241407898
Date:
11-Jun-01     Release date:   02-Nov-01    
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.
323 a.a.
Protein chain
Pfam   ArchSchema ?
Q02293  (FNTB_RAT) -  Protein farnesyltransferase subunit beta from Rattus norvegicus
Seq:
Struc: 		437 a.a.
407 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 = FII)
matches with 50.00% similarity 		+ (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 = FII)
matches with 43.24% 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: 10.1073/pnas.241407898 Proc Natl Acad Sci U S A 98:12948-12953 (2001)
PubMed id: 11687658  
 
 
The crystal structure of human protein farnesyltransferase reveals the basis for inhibition by CaaX tetrapeptides and their mimetics.
S.B.Long, P.J.Hancock, A.M.Kral, H.W.Hellinga, L.S.Beese.
 
  ABSTRACT  
 
Protein farnesyltransferase (FTase) catalyzes the attachment of a farnesyl lipid group to the cysteine residue located in the C-terminal tetrapeptide of many essential signal transduction proteins, including members of the Ras superfamily. Farnesylation is essential both for normal functioning of these proteins, and for the transforming activity of oncogenic mutants. Consequently FTase is an important target for anti-cancer therapeutics. Several FTase inhibitors are currently undergoing clinical trials for cancer treatment. Here, we present the crystal structure of human FTase, as well as ternary complexes with the TKCVFM hexapeptide substrate, CVFM non-substrate tetrapeptide, and L-739,750 peptidomimetic with either farnesyl diphosphate (FPP), or a nonreactive analogue. These structures reveal the structural mechanism of FTase inhibition. Some CaaX tetrapeptide inhibitors are not farnesylated, and are more effective inhibitors than farnesylated CaaX tetrapeptides. CVFM and L-739,750 are not farnesylated, because these inhibitors bind in a conformation that is distinct from the TKCVFM hexapeptide substrate. This non-substrate binding mode is stabilized by an ion pair between the peptide N terminus and the alpha-phosphate of the FPP substrate. Conformational mapping calculations reveal the basis for the sequence specificity in the third position of the CaaX motif that determines whether a tetrapeptide is a substrate or non-substrate. The presence of beta-branched amino acids in this position prevents formation of the non-substrate conformation; all other aliphatic amino acids in this position are predicted to form the non-substrate conformation, provided their N terminus is available to bind to the FPP alpha-phosphate. These results may facilitate further development of FTase inhibitors.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Chemical structures. 		Figure 2.
Fig. 2. Structure of human FTase in complex with the CIFM-derived L-739,750 peptidomimetic and FPP substrate. (A) Overall structure. (B) 6 F[O]-F[C] omit electron density for L-739,750. The FPP substrate and zinc ion are included for reference. (C) Residues forming van der Waals interactions with L-739,750, shown in stereo. The N terminus of the peptidomimetic forms an ion pair with an -phosphate oxygen of the FPP substrate.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21440964 Y.Qiao, J.Gao, Y.Qiu, L.Wu, F.Guo, K.K.Lo, and D.Li (2011).
Design, synthesis, and characterization of piperazinedione-based dual protein inhibitors for both farnesyltransferase and geranylgeranyltransferase-I.
  Eur J Med Chem, 46, 2264-2273.  
  21346865 A.H.Khan, A.Prakash, D.Kumar, A.K.Rawat, R.Srivastava, and S.Srivastava (2010).
Virtual screening and pharmacophore studies for ftase inhibitors using Indian plant anticancer compounds database.
  Bioinformation, 5, 62-66.  
19878682 J.L.Hougland, K.A.Hicks, H.L.Hartman, R.A.Kelly, T.J.Watt, and C.A.Fierke (2010).
Identification of novel peptide substrates for protein farnesyltransferase reveals two substrate classes with distinct sequence selectivities.
  J Mol Biol, 395, 176-190.  
19954434 M.L.Hovlid, R.L.Edelstein, O.Henry, J.Ochocki, A.DeGraw, S.Lenevich, T.Talbot, V.G.Young, A.W.Hruza, F.Lopez-Gallego, N.P.Labello, C.L.Strickland, C.Schmidt-Dannert, and M.D.Distefano (2010).
Synthesis, properties, and applications of diazotrifluropropanoyl-containing photoactive analogs of farnesyl diphosphate containing modified linkages for enhanced stability.
  Chem Biol Drug Des, 75, 51-67.
PDB code: 3ksl
20822181 S.Fletcher, E.P.Keaney, C.G.Cummings, M.A.Blaskovich, M.A.Hast, M.P.Glenn, S.Y.Chang, C.J.Bucher, R.J.Floyd, W.P.Katt, M.H.Gelb, W.C.Van Voorhis, L.S.Beese, S.M.Sebti, and A.D.Hamilton (2010).
Structure-based design and synthesis of potent, ethylenediamine-based, mammalian farnesyltransferase inhibitors as anticancer agents.
  J Med Chem, 53, 6867-6888.  
19199818 J.L.Hougland, C.L.Lamphear, S.A.Scott, R.A.Gibbs, and C.A.Fierke (2009).
Context-dependent substrate recognition by protein farnesyltransferase.
  Biochemistry, 48, 1691-1701.  
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
19447628 O.Henry, F.Lopez-Gallego, S.A.Agger, C.Schmidt-Dannert, S.Sen, D.Shintani, K.Cornish, and M.D.Distefano (2009).
A versatile photoactivatable probe designed to label the diphosphate binding site of farnesyl diphosphate utilizing enzymes.
  Bioorg Med Chem, 17, 4797-4805.  
19301336 S.F.Sousa, P.A.Fernandes, and M.J.Ramos (2009).
The search for the mechanism of the reaction catalyzed by farnesyltransferase.
  Chemistry, 15, 4243-4247.  
18713740 M.A.Hast, and L.S.Beese (2008).
Structure of protein geranylgeranyltransferase-I from the human pathogen Candida albicans complexed with a lipid substrate.
  J Biol Chem, 283, 31933-31940.
PDB code: 3dra
18686940 S.Fletcher, C.G.Cummings, K.Rivas, W.P.Katt, C.Hornéy, F.S.Buckner, D.Chakrabarti, S.M.Sebti, M.H.Gelb, W.C.Van Voorhis, and A.D.Hamilton (2008).
Potent, Plasmodium-selective farnesyltransferase inhibitors that arrest the growth of malaria parasites: structure-activity relationships of ethylenediamine-analogue scaffolds and homology model validation.
  J Med Chem, 51, 5176-5197.  
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.  
17979291 G.R.Labadie, R.Viswanathan, and C.D.Poulter (2007).
Farnesyl diphosphate analogues with omega-bioorthogonal azide and alkyne functional groups for protein farnesyl transferase-catalyzed ligation reactions.
  J Org Chem, 72, 9291-9297.  
17376731 J.Penner-Hahn (2007).
Zinc-promoted alkyl transfer: a new role for zinc.
  Curr Opin Chem Biol, 11, 166-171.  
17912382 R.M.de Figueiredo, L.Coudray, and J.Dubois (2007).
Synthesis and biological evaluation of potential bisubstrate inhibitors of protein farnesyltransferase. Design and synthesis of functionalized imidazoles.
  Org Biomol Chem, 5, 3299-3309.  
17068802 S.F.Sousa, P.A.Fernandes, and M.J.Ramos (2007).
Theoretical studies on farnesyltransferase: the distances paradox explained.
  Proteins, 66, 205-218.  
17046164 G.Pentheroudakis, and N.Pavlidis (2006).
Perspectives for targeted therapies in cancer of unknown primary site.
  Cancer Treat Rev, 32, 637-644.  
16446806 J.Ohkanda, C.L.Strickland, M.A.Blaskovich, D.Carrico, J.W.Lockman, A.Vogt, C.J.Bucher, J.Sun, Y.Qian, D.Knowles, E.E.Pusateri, S.M.Sebti, and A.D.Hamilton (2006).
Structure-based design of imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase.
  Org Biomol Chem, 4, 482-492.  
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.  
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.  
15611883 S.F.Sousa, P.A.Fernandes, and M.J.Ramos (2005).
Unraveling the mechanism of the farnesyltransferase enzyme.
  J Biol Inorg Chem, 10, 3.  
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
12042705 D.T.Le, and K.M.Shannon (2002).
Ras processing as a therapeutic target in hematologic malignancies.
  Curr Opin Hematol, 9, 308-315.  
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
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 code is shown on the right.

 

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