PDBsum entry 1v0b

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protein links
Transferase PDB id
Protein chains
287 a.a. *
262 a.a. *
Waters ×314
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of the t198a mutant of pfpk5
Structure: Cell division control protein 2 homolog. Chain: a, b. Synonym: pfpk5. Engineered: yes. Mutation: yes
Source: Plasmodium falciparum. Organism_taxid: 5833. Expressed in: escherichia coli. Expression_system_taxid: 562
2.2Å     R-factor:   0.226     R-free:   0.275
Authors: S.Holton,A.Merckx,D.Burgess,C.Doerig,M.Noble,J.Endicott
Key ref:
S.Holton et al. (2003). Structures of P. falciparum PfPK5 test the CDK regulation paradigm and suggest mechanisms of small molecule inhibition. Structure, 11, 1329-1337. PubMed id: 14604523 DOI: 10.1016/j.str.2003.09.020
26-Mar-04     Release date:   31-Mar-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q07785  (CDC2H_PLAFK) -  Cell division control protein 2 homolog
288 a.a.
287 a.a.*
Protein chain
Pfam   ArchSchema ?
Q07785  (CDC2H_PLAFK) -  Cell division control protein 2 homolog
288 a.a.
262 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class 1: Chains A, B: E.C.  - Cyclin-dependent kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
+ protein
+ phosphoprotein
   Enzyme class 2: Chains A, B: E.C.  - [RNA-polymerase]-subunit kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + [DNA-directed RNA polymerase] = ADP + [DNA-directed RNA polymerase] phosphate
+ [DNA-directed RNA polymerase]
+ [DNA-directed RNA polymerase] phosphate
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     cytoplasm   1 term 
  Biological process     regulation of cell cycle   3 terms 
  Biochemical function     nucleotide binding     9 terms  


DOI no: 10.1016/j.str.2003.09.020 Structure 11:1329-1337 (2003)
PubMed id: 14604523  
Structures of P. falciparum PfPK5 test the CDK regulation paradigm and suggest mechanisms of small molecule inhibition.
S.Holton, A.Merckx, D.Burgess, C.Doerig, M.Noble, J.Endicott.
Plasmodium falciparum cell cycle regulators are promising targets for antimalarial drug design. We have determined the structure of PfPK5, the first structure of a P. falciparum protein kinase and the first of a cyclin-dependent kinase (CDK) not derived from humans. The fold and the mechanism of inactivation of monomeric CDKs are highly conserved across evolution. ATP-competitive CDK inhibitors have been developed as potential leads for cancer therapeutics. These studies have identified regions of the CDK active site that can be exploited to achieve significant gains in inhibitor potency and selectivity. We have cocrystallized PfPK5 with three inhibitors that target such regions. The sequence differences between PfPK5 and human CDKs within these inhibitor binding sites suggest that selective inhibition is an attainable goal. Such compounds will be useful tools for P. falciparum cell cycle studies, and will provide lead compounds for antimalarial drug development.
  Selected figure(s)  
Figure 1.
Figure 1. PfPK5 Sequence and Fold(A) Alignment of PfPK5 with selected CDKs. PfPK5 (Swissprot accession number Q07785) was aligned with selected CDK sequences (human CDK2 [P24941], S. pombe Cdc2 [P04551], S. cerevisiae CDC28 [P00546], H. sapien CDK6 [Q00534], H. sapien CDK5 [Q00535], and T. brucei tbcrk1 [s05853]), using the program CLUSTAL-W (Thompson et al., 1994), and rendered with the program Alscript (Barton, 1993) (numbered as for PfPK5). Key sequence motifs are highlighted: glycines of the kinase GXGXXG motif, magenta; residues subject to regulatory phosphorylation in CDK1, red; CDK6 residues that contact p16^INK4A, light blue (Russo et al., 1998); residues delineating the activation loop, cyan; residues equivalent to CDK5 153, a key CDK2/CDK5 sequence difference, salmon (Tarricone et al., 2001); GDSEID motif, involved in both CKS1 (Bourne et al., 1996) and KAP binding (Song et al., 2001), dark blue; other residues that contact KAP or CKS proteins, turquoise; the kinase insert region, and CDK insert region, areas of hypervariability between kinases are boxed (Hanks and Hunter, 1995). Residues shaded in yellow are highly conserved between all CDKs.(B) The monomeric PfPK5 fold. The N-terminal domain (residues 1-82) is colored white and the C-terminal domain (residues 83-288) gold. The glycine-rich loop (residues 10-19), the C helix (residues 39-56), and the activation loop (residues 143-170 from the conserved DFG to APE motifs) are colored magenta, red, and cyan respectively. PfPK5 residues Asp125, Asn130, and Asp143 are drawn in ball-and-stick mode and are discussed in the main text.(C) Overlay of the structures of monomeric PfPK5Thr198Ala and CDK2 in the vicinity of the activation loop. CDK2 has been superimposed, colored green (De Bondt et al., 1993). The CDK2 activation loop forms a b hairpin that turns across the end of the glycine loop, while the activation loop of PfPK5^Thr198Ala adopts an extended structure as it stretches away from aL12 into a short a helix of 2.5 turns.
  The above figure is reprinted by permission from Cell Press: Structure (2003, 11, 1329-1337) copyright 2003.  
  Figure was selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21287607 J.M.Hayes, V.T.Skamnaki, G.Archontis, C.Lamprakis, J.Sarrou, N.Bischler, A.L.Skaltsounis, S.E.Zographos, and N.G.Oikonomakos (2011).
Kinetics, in silico docking, molecular dynamics, and MM-GBSA binding studies on prototype indirubins, KT5720, and staurosporine as phosphorylase kinase ATP-binding site inhibitors: The role of water molecules examined.
  Proteins, 79, 703-719.  
20663247 N.Wurtz, C.Chapus, J.Desplans, and D.Parzy (2011).
cAMP-dependent protein kinase from Plasmodium falciparum: an update.
  Parasitology, 138, 1.  
20305001 J.Halbert, L.Ayong, L.Equinet, K.Le Roch, M.Hardy, D.Goldring, L.Reininger, N.Waters, D.Chakrabarti, and C.Doerig (2010).
A Plasmodium falciparum transcriptional cyclin-dependent kinase-related kinase with a crucial role in parasite proliferation associates with histone deacetylase activity.
  Eukaryot Cell, 9, 952-959.  
20575139 K.Engels, C.Beyer, M.L.Suárez Fernández, F.Bender, M.Gassel, G.Unden, R.J.Marhöfer, J.C.Mottram, and P.M.Selzer (2010).
Inhibition of Eimeria tenella CDK-related kinase 2: From target identification to lead compounds.
  ChemMedChem, 5, 1259-1271.  
  20951971 R.Tewari, U.Straschil, A.Bateman, U.Böhme, I.Cherevach, P.Gong, A.Pain, and O.Billker (2010).
The systematic functional analysis of Plasmodium protein kinases identifies essential regulators of mosquito transmission.
  Cell Host Microbe, 8, 377-387.  
19393157 F.C.Koyama, D.Chakrabarti, and C.R.Garcia (2009).
Molecular machinery of signal transduction and cell cycle regulation in Plasmodium.
  Mol Biochem Parasitol, 165, 1-7.  
19132059 H.Nakano, and S.Omura (2009).
Chemical biology of natural indolocarbazole products: 30 years since the discovery of staurosporine.
  J Antibiot (Tokyo), 62, 17-26.  
18394721 D.Leroy, and C.Doerig (2008).
Drugging the Plasmodium kinome: the benefits of academia-industry synergy.
  Trends Pharmacol Sci, 29, 241-249.  
18816110 K.Vougogiannopoulou, Y.Ferandin, K.Bettayeb, V.Myrianthopoulos, O.Lozach, Y.Fan, C.H.Johnson, P.Magiatis, A.L.Skaltsounis, E.Mikros, and L.Meijer (2008).
Soluble 3',6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase -3 alter circadian period.
  J Med Chem, 51, 6421-6431.  
18828893 L.M.Birkholtz, G.Blatch, T.L.Coetzer, H.C.Hoppe, E.Human, E.J.Morris, Z.Ngcete, L.Oldfield, R.Roth, A.Shonhai, L.Stephens, and A.I.Louw (2008).
Heterologous expression of plasmodial proteins for structural studies and functional annotation.
  Malar J, 7, 197.  
17298288 C.Doerig, and L.Meijer (2007).
Antimalarial drug discovery: targeting protein kinases.
  Expert Opin Ther Targets, 11, 279-290.  
16702956 J.Ribas, K.Bettayeb, Y.Ferandin, M.Knockaert, X.Garrofé-Ochoa, F.Totzke, C.Schächtele, J.Mester, P.Polychronopoulos, P.Magiatis, A.L.Skaltsounis, J.Boix, and L.Meijer (2006).
7-Bromoindirubin-3'-oxime induces caspase-independent cell death.
  Oncogene, 25, 6304-6318.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
15752424 A.G.Schneider, and O.Mercereau-Puijalon (2005).
A new Apicomplexa-specific protein kinase family: multiple members in Plasmodium falciparum, all with an export signature.
  BMC Genomics, 6, 30.  
15515182 Anamika, N.Srinivasan, and A.Krupa (2005).
A genomic perspective of protein kinases in Plasmodium falciparum.
  Proteins, 58, 180-189.  
16096806 K.K.Manhani, H.A.Arcuri, N.J.da Silveira, H.B.Uchôa, Azevedo, and F.Canduri (2005).
Molecular models of protein kinase 6 from Plasmodium falciparum.
  J Mol Model, 12, 42-48.  
15479470 P.Ward, L.Equinet, J.Packer, and C.Doerig (2004).
Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote.
  BMC Genomics, 5, 79.  
15057931 R.J.Wilson (2004).
The transcriptome: malariologists ride the wave.
  Bioessays, 26, 339-342.  
14604516 L.S.Brinen, and T.J.Stout (2003).
Can mosquitoes be bitten? A new hope for anti-malarial drug design.
  Structure, 11, 1309-1310.  
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.