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PDBsum entry 1d8d

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
1d8d
Jmol
Contents
Protein chains
323 a.a. *
407 a.a. *
11 a.a. *
Ligands
ACT ×4
FII
Metals
_ZN
Waters ×447
* Residue conservation analysis
PDB id:
1d8d
Name: Transferase
Title: Co-crystal structure of rat protein farnesyltransferase complexed with a k-ras4b peptide substrate and fpp analog at 2.0a resolution
Structure: Farnesyltransferase (alpha subunit). Chain: a. Fragment: alpha subunit. Synonym: ftase. Engineered: yes. Farnesyltransferase (beta subunit). Chain: b. Fragment: beta subunit. Synonym: ftase.
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Organ: brain. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_atcc_number: 63134. Synthetic: yes. Other_details: this synthetic peptide is derived from
Biol. unit: Trimer (from PQS)
Resolution:
2.00Å     R-factor:   0.164     R-free:   0.200
Authors: S.B.Long,P.J.Casey,L.S.Beese
Key ref:
S.B.Long et al. (2000). The basis for K-Ras4B binding specificity to protein farnesyltransferase revealed by 2 A resolution ternary complex structures. Structure, 8, 209-222. PubMed id: 10673434 DOI: 10.1016/S0969-2126(00)00096-4
Date:
22-Oct-99     Release date:   09-Feb-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q04631  (FNTA_RAT) -  Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha
Seq:
Struc:
377 a.a.
323 a.a.
Protein chain
Pfam   ArchSchema ?
Q02293  (FNTB_RAT) -  Protein farnesyltransferase subunit beta
Seq:
Struc:
437 a.a.
407 a.a.
Protein chain
Pfam   ArchSchema ?
P01116  (RASK_HUMAN) -  GTPase KRas
Seq:
Struc:
189 a.a.
11 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 7 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class 2: Chains A, B: E.C.2.5.1.58  - Protein farnesyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Farnesyl diphosphate + protein-cysteine = S-farnesyl protein + diphosphate
Farnesyl diphosphate
Bound ligand (Het Group name = FII)
matches with 50.00% similarity
+ protein-cysteine
= S-farnesyl protein
+ diphosphate
      Cofactor: Mg(2+); Zn(2+)
   Enzyme class 3: Chain A: E.C.2.5.1.59  - Protein geranylgeranyltransferase type I.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl- protein + diphosphate
Geranylgeranyl diphosphate
Bound ligand (Het Group name = FII)
matches with 43.00% similarity
+ protein-cysteine
= S-geranylgeranyl- 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
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     protein complex   5 terms 
  Biological process     response to inorganic substance   15 terms 
  Biochemical function     catalytic activity     14 terms  

 

 
    reference    
 
 
DOI no: 10.1016/S0969-2126(00)00096-4 Structure 8:209-222 (2000)
PubMed id: 10673434  
 
 
The basis for K-Ras4B binding specificity to protein farnesyltransferase revealed by 2 A resolution ternary complex structures.
S.B.Long, P.J.Casey, L.S.Beese.
 
  ABSTRACT  
 
Background: The protein farnesyltransferase (FTase) catalyzes addition of the hydrophobic farnesyl isoprenoid to a cysteine residue fourth from the C terminus of several protein acceptors that are essential for cellular signal transduction such as Ras and Rho. This addition is necessary for the biological function of the modified proteins. The majority of Ras-related human cancers are associated with oncogenic variants of K-RasB, which is the highest affinity natural substrate of FTase. Inhibition of FTase causes regression of Ras-mediated tumors in animal models. Results: We present four ternary complexes of rat FTase co-crystallized with farnesyl diphosphate analogs and K-Ras4B peptide substrates. The Ca(1)a(2)X portion of the peptide substrate binds in an extended conformation in the hydrophobic cavity of FTase and coordinates the active site zinc ion. These complexes offer the first view of the polybasic region of the K-Ras4B peptide substrate, which confers the major enhancement of affinity of this substrate. The polybasic region forms a type I beta turn and binds along the rim of the hydrophobic cavity. Removal of the catalytically essential zinc ion results in a dramatically different peptide conformation in which the Ca(1)a(2)X motif adopts a beta turn. A manganese ion binds to the diphosphate mimic of the farnesyl diphosphate analog. Conclusions: These ternary complexes provide new insight into the molecular basis of peptide substrate specificity, and further define the roles of zinc and magnesium in the prenyltransferase reaction. Zinc is essential for productive Ca(1)a(2)X peptide binding, suggesting that the beta-turn conformation identified in previous nuclear magnetic resonance (NMR) studies reflects a state in which the cysteine is not coordinated to the zinc ion. The structural information presented here should facilitate structure-based design and optimization of inhibitors of Ca(1)a(2)X protein prenyltransferases.
 
  Selected figure(s)  
 
Figure 6.
Figure 6. b-Turn conformation of the Ca[1]a[2]X box of the peptide (yellow) bound to zinc-depleted FTase. The zinc-coordinated conformation (light blue) is superimposed. This view is approximately the same as that shown in Figure 4.
 
  The above figure is reprinted by permission from Cell Press: Structure (2000, 8, 209-222) copyright 2000.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
20432425 U.T.Nguyen, R.S.Goody, and K.Alexandrov (2010).
Understanding and exploiting protein prenyltransferases.
  Chembiochem, 11, 1194-1201.  
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
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.  
18844669 A.J.DeGraw, M.A.Hast, J.Xu, D.Mullen, L.S.Beese, G.Barany, and M.D.Distefano (2008).
Caged protein prenyltransferase substrates: tools for understanding protein prenylation.
  Chem Biol Drug Des, 72, 171-181.
PDB code: 3dpy
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
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.  
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.  
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
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.  
16983387 M.H.Gelb, L.Brunsveld, C.A.Hrycyna, S.Michaelis, F.Tamanoi, W.C.Van Voorhis, and H.Waldmann (2006).
Therapeutic intervention based on protein prenylation and associated modifications.
  Nat Chem Biol, 2, 518-528.  
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.  
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.  
15960807 S.Maurer-Stroh, and F.Eisenhaber (2005).
Refinement and prediction of protein prenylation motifs.
  Genome Biol, 6, R55.  
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.  
15131129 H.L.Hartman, K.E.Bowers, and C.A.Fierke (2004).
Lysine beta311 of protein geranylgeranyltransferase type I partially replaces magnesium.
  J Biol Chem, 279, 30546-30553.  
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
12702202 S.Maurer-Stroh, S.Washietl, and F.Eisenhaber (2003).
Protein prenyltransferases.
  Genome Biol, 4, 212.  
11847292 J.Pei, and N.V.Grishin (2002).
Breaking the singleton of germination protease.
  Protein Sci, 11, 691-697.  
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
  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
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.