1URC

Cyclin A binding groove inhibitor Ace-Arg-Lys-Leu-Phe-Gly

Summary for 1URC

• Entry DOI: 10.2210/pdb1urc/pdb
• Related: 1AQ1 1B38 1B39 1BUH 1CKP 1DI8 1DM2 1E1V 1E1X 1E9H 1F5Q 1FIN 1FQ1 1FVT 1FVV 1G5S 1GIH 1GII 1GIJ 1GY3 1GZ8 1H00 1H01 1H06 1H07 1H08 1H0U 1H0V 1H0W 1H1P 1H1Q 1H1R 1H1S 1H24 1H25 1H26 1H27 1H28 1HCK 1HCL 1JST 1JSU 1JSV 1JVP 1KE5 1KE6 1KE7 1KE8 1KE9 1OGU 1OI9 1OIQ 1OIR 1OIT 1OIU 1OIY 1OKU 1OKV 1OKW 1OL1 1OL2 1P2A 1P5E 1PKD 1QMZ
• Descriptor: CELL DIVISION PROTEIN KINASE 2, CYCLIN A2, PEPTIDE INHIBITOR, ... (4 entities in total)
• Functional Keywords: transferase-inhibitor complex, inhibitor, ligand exchange, drug design, peptidomimetics, transferase/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 128983.62

Authors

Kontopidis, G.,Andrews, M.,McInnes, C.,Cowan, A.,Powers, H.,Innes, L.,Plater, A.,Griffiths, G.,Paterson, D.,Zheleva, D.,Lane, D.,Green, S.,Walkinshaw, M.,Fischer, P. (deposition date: 2003-10-28, release date: 2003-10-31, Last modification date: 2023-12-13)

Primary citation

Andrews, M.J.,McInnes, C.,Kontopidis, G.,Innes, L.,Cowan, A.,Plater, A.,Fischer, P.M.
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, 2004

PubMed 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.

PubMed: 15455144
DOI: 10.1039/B409157D

Experimental method

X-RAY DIFFRACTION (2.6 Å)