PDBsum entry 1v0p

Transferase

PDB id: 1v0p

Contents

Protein chains

277 a.a. *

258 a.a. *

Ligands

PVB ×2

Waters ×239

* Residue conservation analysis

PDB id:

1v0p

Name:

Transferase

Title:

Structure of p. Falciparum pfpk5-purvalanol b ligand complex

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

Resolution:

2.00Å R-factor: 0.198 R-free: 0.265

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

Date:

01-Apr-04 Release date: 06-May-04

Protein chain

Q07785  (CDK2H_PLAFK) -  Cyclin-dependent kinase 2 homolog from Plasmodium falciparum (isolate K1 / Thailand)

Seq: 288 a.a.

Struc: 277 a.a.

Protein chain

Q07785  (CDK2H_PLAFK) -  Cyclin-dependent kinase 2 homolog from Plasmodium falciparum (isolate K1 / Thailand)

Seq: 288 a.a.

Struc: 258 a.a.

Enzyme reactions

• Enzyme class 1: Chains A, B: E.C.2.7.11.22 - cyclin-dependent kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺
• Enzyme class 2: Chains A, B: E.C.2.7.11.23 - [RNA-polymerase]-subunit kinase.
• Reaction: [DNA-directed RNA polymerase] + ATP = phospho-[DNA-directed RNA polymerase] + ADP + H⁺

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: 10.1016/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.

ABSTRACT

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.