1H0V

Human cyclin dependent protein kinase 2 in complex with the inhibitor 2-Amino-6-[(R)-pyrrolidino-5'-yl]methoxypurine

Summary for 1H0V

• Entry DOI: 10.2210/pdb1h0v/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 1H0W 1HCK 1HCL 1JST 1JSU 1JSV 1JVP 1QMZ
• Descriptor: CELL DIVISION PROTEIN KINASE 2, 5-{[(2-AMINO-9H-PURIN-6-YL)OXY]METHYL}-2-PYRROLIDINONE (3 entities in total)
• Functional Keywords: transferase, drug metabolism, mycobacteria, isoniazid, arylamine n-acetyltransferase, nat, serine/threonine -protein kinase, atp-binding, cell cycle, cell division, mitosis
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 34224.73

Authors

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.M.,Tucker, J.A.,Whitfield, H.J. (deposition date: 2002-06-27, release date: 2003-06-27, Last modification date: 2023-12-13)

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.M.,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 (1.9 Å)