PDBsum entry 1urc

Transferase/inhibitor

PDB id: 1urc

Contents

Protein chains

296 a.a. *

258 a.a. *

Ligands

ACE-ARG-LYS-LEU-PHE-GLY ×2

Waters ×338

* Residue conservation analysis

PDB id:

1urc

Name:

Transferase/inhibitor

Title:

Cyclin a binding groove inhibitor ace-arg-lys-leu-phe-gly

Structure:

Cell division protein kinase 2. Chain: a, c. Synonym: p33 protein kinase, cdk2, cyclin-dependent kinase-2. Engineered: yes. Cyclin a2. Chain: b, d. Fragment: residues 173 - 432. Synonym: cyclin a, ccna2, ccna, ccn1. Engineered: yes.

Source:

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

Biol. unit:

Trimer (from PDB file)

Resolution:

2.60Å R-factor: 0.177 R-free: 0.254

Authors:

G.Kontopidis,M.Andrews,C.Mcinnes,A.Cowan,H.Powers,L.Innes,A.Plater, G.Griffiths,D.Paterson,D.Zheleva,D.Lane,S.Green,M.Walkinshaw, P.Fischer

Key ref:

M.J.Andrews et al. (2004). Design, synthesis, biological activity and structural analysis of cyclic peptide inhibitors targeting the substrate recruitment site of cyclin-dependent kinase complexes. Org Biomol Chem, 2, 2735-2741. PubMed id: 15455144

Date:

28-Oct-03 Release date: 31-Oct-03

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

Org Biomol Chem 2:2735-2741 (2004)

PubMed id: 15455144

Design, synthesis, biological activity and structural analysis of cyclic peptide inhibitors targeting the substrate recruitment site of cyclin-dependent kinase complexes.

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

ABSTRACT

Inhibition of cyclin A- and cyclin E-associated cyclin-dependent kinase-2 (CDK2) activities is an effective way of selective induction of apoptotic cell death via the E2F pathway in tumour cells. The cyclin groove recognition motif (CRM) in the natural CDK-inhibitory (CDKI) tumour suppressor protein p27KIP1 was used as the basis for the design and synthesis of a series of cyclic peptides whose biological activity and structural characterisation by NMR and X-ray crystallography is reported. Whereas linear p27KIP1 sequence peptides were comparatively ineffective, introduction of side chain-to-tail constraints was found to be productive. An optimal macrocyclic ring size for the conformational constraint was determined, mimicking the intramolecular H-bonding system of p27. Molecular dynamics calculations of various macrocycles suggested a close correlation between ring flexibility and biological activity. Truncated inhibitor peptide analogues also confirmed the hypothesis that introduction of a cyclic conformational constraint is favourable in terms of affinity and potency. The structural basis for the potency increase in cyclic versus linear peptides was demonstrated through the determination and interpretation of X-ray crystal structures of complexes between CDK2/cylin A (CDK2A) and a constrained pentapeptide.