PDBsum entry 2wev

Transferase

PDB id: 2wev

Contents

Protein chains

296 a.a. *

258 a.a. *

Ligands

ACE-ARG-ARG-B3L-MEA-NH2 ×2

CK7 ×2

Waters ×545

* Residue conservation analysis

PDB id:

2wev

Name:

Transferase

Title:

Truncation and optimisation of peptide inhibitors of cdk2, cyclin a through structure guided design

Structure:

Cell division protein kinase 2. Chain: a, c. Synonym: cyclin-dependent kinase 2, p33 protein kinase. Engineered: yes. Other_details: triazol-1-methyl-pyrimidin inhibitor. Cyclin-a2. Chain: b, d. Fragment: residues 173-432. Synonym: cyclin-a.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes.

Resolution:

2.30Å R-factor: 0.190 R-free: 0.243

Authors:

G.Kontopidis,M.J.Andrews,C.Mcinnes,A.Plater,L.Innes,S.Renachowski, A.Cowan,P.M.Fischer

Key ref:

G.Kontopidis et al. (2009). Truncation and optimisation of peptide inhibitors of cyclin-dependent kinase 2-cyclin a through structure-guided design. Chemmedchem, 4, 1120-1128. PubMed id: 19472269

Date:

01-Apr-09 Release date: 09-Jun-09

Supersedes:

2c5p

Protein chains

P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2 from Homo sapiens

Seq: 298 a.a.

Struc: 296 a.a.

Protein chains

P20248  (CCNA2_HUMAN) -  Cyclin-A2 from Homo sapiens

Seq: 432 a.a.

Struc: 258 a.a.

Enzyme reactions

• Enzyme class: Chains A, C: 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⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

Chemmedchem 4:1120-1128 (2009)

PubMed id: 19472269

Truncation and optimisation of peptide inhibitors of cyclin-dependent kinase 2-cyclin a through structure-guided design.

G.Kontopidis, M.J.Andrews, C.McInnes, A.Plater, L.Innes, S.Renachowski, A.Cowan, P.M.Fischer.

ABSTRACT

Peptides that inhibit cyclin-dependent kinase 2 by blocking the macromolecular substrate recruitment site of cyclin A were simplified, for example, by replacement of dipeptide units with beta-amino acids. The smallest inhibitor retaining activity was a tripeptide, whose binding mode was confirmed by X-ray crystallography. This result suggests that nonpeptidic cyclin groove inhibitors may be feasible therapeutic agents.The cyclin-dependent kinase 2-cyclin A complex is an important regulator of the DNA-synthesis phase of the mammalian cell cycle, which is frequently deregulated in cancer. Rather than blocking the ATP-binding site of the apparently redundant kinase subunit, targeting the binding site for macromolecular substrates and regulatory proteins of cyclin A represents a promising strategy to enforce tumour-selective apoptosis. The cyclin-binding groove can be blocked with comparatively small synthetic peptides, which indirectly leads to inhibition of kinase function, but these peptides are metabolically labile and membrane impermeable. As part of our ongoing effort to develop more druglike peptidomimetics derived from cyclin-groove-binding peptides, we report the results of our studies aimed at a detailed understanding of the structural determinants required for effective binding. Using a combination of peptide synthesis, biochemical assays and X-ray crystallography, we show that it is possible to simplify peptide structures through the replacement of dipeptide units in which one of the residues is not directly involved in binding, through the introduction of beta-amino acid residues that retain only the dipeptide residue side chain that is important for binding. This approach also allowed us to probe spatial constraints in general, as well as the importance of peptide backbone hydrogen-bonding functions. Our identification of potent beta-homoleucine-containing tetrapeptide inhibitors, as well as the finding that an optimised N-terminally acetylated tripeptide retains some cyclin A-binding affinity, suggest that the pharmacological targeting of the cyclin A binding groove may be feasible.