2WEV

Truncation and Optimisation of Peptide Inhibitors of CDK2, Cyclin A Through Structure Guided Design

Replaces:  2C5P

Summary for 2WEV

• Entry DOI: 10.2210/pdb2wev/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 1H07 1H08 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 1OKV 1OKW 1OL1 1OL2 1P2A 1P5E 1PF8 1PKD 1PW2 1PXI 1PXJ 1PXK 1PXL 1PXM 1PXN 1PXO 1PXP 1PYE 1QMZ 1R78 1URC 1URW 1V1K 1VYW 1VYZ 1W0X 1W8C 1W98 1WCC 1Y8Y 1Y91 1YKR 2A0C 2A4L 2B52 2B53 2B54 2B55 2BHE 2BHH 2BKZ 2BPM 2BTR 2BTS 2C4G 2C5N 2C5O 2C5V 2C5X 2C5Y 2C68 2C69 2C6I 2C6K 2C6L 2C6M 2C6O 2C6T 2CCH 2CCI 2CJM 2CLX 2EXM 2G9X 2IW6 2IW8 2IW9 2J9M 2JGZ 2UUE 2UZB 2UZD 2UZE 2UZL 2UZN 2UZO 2V0D 2V22 2VTA 2VTH 2VTI 2VTJ 2VTL 2VTM 2VTN 2VTO 2VTP 2VTQ 2VTR 2VTS 2VTT 2VU3 2VV9 2W05 2W06 2W17 2W1H
• Descriptor: CELL DIVISION PROTEIN KINASE 2, CYCLIN-A2, ARG-ARG-B3L-MEA, ... (5 entities in total)
• Functional Keywords: cdk2, kinase, cyclin, active, nucleus, mitosis, serine/threonine-protein kinase, cytoplasm, inhibition, cell cycle, atp-binding, cell division, phosphoprotein, nucleotide-binding, transferase, polymorphism, beta-peptide, cyclin groove
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: P24941; Nucleus : P20248
• Total number of polymer chains: 6
• Total formula weight: 129634.37

Authors

Kontopidis, G.,Andrews, M.J.,McInnes, C.,Plater, A.,Innes, L.,Renachowski, S.,Cowan, A.,Fischer, P.M. (deposition date: 2009-04-01, release date: 2009-06-09, Last modification date: 2023-12-13)

Primary citation

Kontopidis, G.,Andrews, M.J.,Mcinnes, C.,Plater, A.,Innes, L.,Renachowski, S.,Cowan, A.,Fischer, P.M.
Truncation and Optimisation of Peptide Inhibitors of Cyclin-Dependent Kinase 2-Cyclin a Through Structure-Guided Design.
Chemmedchem, 4:1120-, 2009

PubMed 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.

PubMed: 19472269
DOI: 10.1002/CMDC.200900093

Experimental method

X-RAY DIFFRACTION (2.3 Å)