1GZ8

HUMAN CYCLIN DEPENDENT KINASE 2 COMPLEXED WITH THE INHIBITOR 2-Amino-6-(3'-methyl-2'-oxo)butoxypurine

Summary for 1GZ8

• Entry DOI: 10.2210/pdb1gz8/pdb
• Related: 1AQ1 1B38 1B39 1BUH 1CKP 1DI8 1DM2 1E1V 1E1X 1E9H 1F5Q 1FIN 1FQ1 1FVT 1FVV 1G5S 1GIH 1GII 1GIJ 1GY3 1HCK 1HCL 1JST 1JSU 1JSV 1JVP 1QMZ
• Descriptor: CELL DIVISION PROTEIN KINASE 2, 1-[(2-AMINO-6,9-DIHYDRO-1H-PURIN-6-YL)OXY]-3-METHYL-2-BUTANOL (3 entities in total)
• Functional Keywords: kinase, protein kinase, cell cycle, phosphorylation, cell division, mitosis, inhibition, transferase, serine/threonine-protein kinase, atp-binding, 3d-structure.
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 34269.77

Authors

Davies, T.,Endicott, J.,Johnson, L.,Noble, M.,Tucker, J. (deposition date: 2002-05-17, release date: 2003-06-12, Last modification date: 2024-10-09)

Primary citation

Gibson, A.E.,Arris, C.E.,Bentley, J.,Boyle, F.T.,Curtin, N.J.,Davies, T.G.,Endicott, J.A.,Golding, B.T.,Grant, S.,Griffin, R.J.,Jewsbury, P.,Johnson, L.N.,Mesguiche, V.,Newell, D.R.,Noble, M.E.,Tucker, J.A.,Whitfield, H.J.
Probing the ATP Ribose-Binding Domain of Cyclin-Dependent Kinases 1 and 2 with O(6)-Substituted Guanine Derivatives
J.Med.Chem., 45:3381-, 2002

PubMed Abstract: O(6)-substituted guanines are adenosine 5'-triphosphate (ATP) competitive inhibitors of CDK1/cyclin B1 and CDK2/cyclin A, the O(6) substituent occupying the kinase ribose binding site. Fifty-eight O(6)-substituted guanines were prepared to probe the ribose pocket, and the structures of four representative compounds bound to monomeric CDK2 were determined by X-ray crystallography. Optimum binding occurs with a moderately sized aliphatic O(6) substituent that packs tightly against the hydrophobic patch presented by the glycine loop, centered on Val18, an interaction promoted by the conformational restraints imposed in a cyclohexylmethyl or cyclohexenylmethyl ring. Structure-based design generated (R)-(2-amino-9H-purin-6-yloxymethyl)pyrrolidin-2-one (56), which reproduces the reported hydrogen bonds formed between ATP and Asp86 and Gln131 but failed to improve inhibitory potency. Thus, the parent compound O(6)-cyclohexylmethylguanine (NU2058, 25) is the preferred starting point for exploring other areas of the kinase active site.

PubMed: 12139449
DOI: 10.1021/JM020056Z

Experimental method

X-RAY DIFFRACTION (1.3 Å)