1urc
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CYCLIN A BINDING GROOVE INHIBITOR ACE-ARG-LYS-LEU-PHE-GLY
OverviewOverview
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.
About this StructureAbout this Structure
1URC is a Protein complex structure of sequences from Homo sapiens with ACE as ligand. Active as Transferred entry: 2.7.11.1, with EC number 2.7.1.37 Structure known Active Site: CBG. Full crystallographic information is available from OCA.
ReferenceReference
Design, synthesis, biological activity and structural analysis of cyclic peptide inhibitors targeting the substrate recruitment site of cyclin-dependent kinase complexes., Andrews MJ, McInnes C, Kontopidis G, Innes L, Cowan A, Plater A, Fischer PM, Org Biomol Chem. 2004 Oct 7;2(19):2735-41. Epub 2004 Sep 9. PMID:15455144
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