2CCH

The crystal structure of CDK2 cyclin A in complex with a substrate peptide derived from CDC modified with a gamma-linked ATP analogue

Summary for 2CCH

• Entry DOI: 10.2210/pdb2cch/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 1OKU 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 2B52 2B53 2B54 2B55 2BHE 2BHH 2BKZ 2BPM 2BTR 2BTS 2C4G 2C5N 2C5O 2C5P 2C5T 2C5V 2C5X 2C5Y 2C68 2C69 2C6I 2C6K 2C6L 2C6M 2C6O 2C6T 2EXM
• Descriptor: CELL DIVISION PROTEIN KINASE 2, CYCLIN A2, CELL DIVISION CONTROL PROTEIN 6 HOMOLOG, ... (7 entities in total)
• Functional Keywords: complex(transferase-cell division), atp-binding, cdk2, cell cycle, cell division, cyclin, mitosis, nuclear protein, peptide specificity, phosphorylation, polymorphism, protein kinase, recruitment, serine-threonine-protein kinase, serine/threonine-protein kinase, transferase
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 6
• Total formula weight: 132236.12

Authors

Cheng, K.Y.,Noble, M.E.M.,Skamnaki, V.,Brown, N.R.,Lowe, E.D.,Kontogiannis, L.,Shen, K.,Cole, P.A.,Siligardi, G.,Johnson, L.N. (deposition date: 2006-01-16, release date: 2006-05-03, Last modification date: 2023-12-13)

Primary citation

Cheng, K.Y.,Noble, M.E.M.,Skamnaki, V.,Brown, N.R.,Lowe, E.D.,Kontogiannis, L.,Shen, K.,Cole, P.A.,Siligardi, G.,Johnson, L.N.
The Role of the Phospho-Cdk2/Cyclin a Recruitment Site in Substrate Recognition
J.Biol.Chem., 281:23167-, 2006

PubMed Abstract: Phospho-CDK2/cyclin A, a kinase that is active in cell cycle S phase, contains an RXL substrate recognition site that is over 40 A from the catalytic site. The role of this recruitment site, which enhances substrate affinity and catalytic efficiency, has been investigated using peptides derived from the natural substrates, namely CDC6 and p107, and a bispeptide inhibitor in which the gamma-phosphate of ATP is covalently attached by a linker to the CDC6 substrate peptide. X-ray studies with a 30-residue CDC6 peptide in complex with pCDK2/cyclin A showed binding of a dodecamer peptide at the recruitment site and a heptapeptide at the catalytic site, but no density for the linking 11 residues. Kinetic studies established that the CDC6 peptide had an 18-fold lower Km compared with heptapeptide substrate and that this effect required the recruitment peptide to be covalently linked to the substrate peptide. X-ray studies with the CDC6 bispeptide showed binding of the dodecamer at the recruitment site and the modified ATP in two alternative conformations at the catalytic site. The CDC6 bispeptide was a potent inhibitor competitive with both ATP and peptide substrate of pCDK2/cyclin A activity against a heptapeptide substrate (Ki = 0.83 nm) but less effective against RXL-containing substrates. We discuss how localization at the recruitment site (KD 0.4 microm) leads to increased catalytic efficiency and the design of a potent inhibitor. The notion of a flexible linker between the sites, which must have more than a minimal number of residues, provides an explanation for recognition and discrimination against different substrates.

PubMed: 16707497
DOI: 10.1074/JBC.M600480200

Experimental method

X-RAY DIFFRACTION (1.7 Å)