1H1P

Structure of human Thr160-phospho CDK2/cyclin A complexed with the inhibitor NU2058

Summary for 1H1P

• Entry DOI: 10.2210/pdb1h1p/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 1H1Q 1H1R 1H1S 1HCK 1HCL 1JST 1JSU 1JSV 1JVP 1KE5 1KE6 1KE7 1KE8 1KE9 1QMZ
• Descriptor: CELL DIVISION PROTEIN KINASE 2, CYCLIN A2, 6-O-CYCLOHEXYLMETHYL GUANINE, ... (4 entities in total)
• Functional Keywords: kinase, transferase, serine/threonine-protein kinase, atp-binding, cell cycle, cell division, mitosis, phosphorylation
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Nucleus: P20248
• Total number of polymer chains: 4
• Total formula weight: 128679.04

Authors

Davies, T.G.,Noble, M.E.M.,Endicott, J.A.,Johnson, L.N. (deposition date: 2002-07-21, release date: 2002-09-19, Last modification date: 2024-10-23)

Primary citation

Davies, T.G.,Bentley, J.,Arris, C.E.,Boyle, F.T.,Curtin, N.J.,Endicott, J.A.,Gibson, A.E.,Golding, B.T.,Griffin, R.J.,Hardcastle, I.R.,Jewsbury, P.,Johnson, L.N.,Mesguiche, V.,Newell, D.R.,Noble, M.E.M.,Tucker, J.A.,Wang, L.,Whitfield, H.J.
Structure-Based Design of a Potent Purine-Based Cyclin-Dependent Kinase Inhibitor
Nat.Struct.Biol., 9:745-, 2002

PubMed Abstract: Aberrant control of cyclin-dependent kinases (CDKs) is a central feature of the molecular pathology of cancer. Iterative structure-based design was used to optimize the ATP- competitive inhibition of CDK1 and CDK2 by O(6)-cyclohexylmethylguanines, resulting in O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino)purine. The new inhibitor is 1,000-fold more potent than the parent compound (K(i) values for CDK1 = 9 nM and CDK2 = 6 nM versus 5,000 nM and 12,000 nM, respectively, for O(6)-cyclohexylmethylguanine). The increased potency arises primarily from the formation of two additional hydrogen bonds between the inhibitor and Asp 86 of CDK2, which facilitate optimum hydrophobic packing of the anilino group with the specificity surface of CDK2. Cellular studies with O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino) purine demonstrated inhibition of MCF-7 cell growth and target protein phosphorylation, consistent with CDK1 and CDK2 inhibition. The work represents the first successful iterative synthesis of a potent CDK inhibitor based on the structure of fully activated CDK2-cyclin A. Furthermore, the potency of O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino)purine was both predicted and fully rationalized on the basis of protein-ligand interactions.

PubMed: 12244298
DOI: 10.1038/NSB842

Experimental method

X-RAY DIFFRACTION (2.1 Å)