PDBsum entry 1h0v

Transferase

PDB id

1h0v

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Contents

			Protein chain

					288 a.a. *

			Ligands

					UN4

			Waters ×310

* Residue conservation analysis

PDB id:

1h0v

Links

Name:

Transferase

Title:

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

Structure:

Cell division protein kinase 2. Chain: a. Synonym: human cyclin-dependent kinase 2, p33 protein kinase, cdk2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

1.90Å

R-factor:

0.158

R-free:

0.234

Authors:

A.E.Gibson,C.E.Arris,J.Bentley,F.T.Boyle,N.J.Curtin,T.G.Davies, J.A.Endicott,B.T.Golding,S.Grant,R.J.Griffin,P.Jewsbury,L.N.Johnson, V.Mesguiche,D.R.Newell,M.E.M.Noble,J.A.Tucker,H.J.Whitfield

Key ref:

A.E.Gibson et al. (2002). Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O(6)-substituted guanine derivatives. J Med Chem, 45, 3381-3393. PubMed id: 12139449 DOI: 10.1021/jm020056z

Date:

27-Jun-02

Release date:

27-Jun-03

PROCHECK

	Headers

	References

Protein chain

P24941 (CDK2_HUMAN) - Cyclin-dependent kinase 2 from Homo sapiens

Seq: Struc:					298 a.a. 288 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.2.7.11.22 - cyclin-dependent kinase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

1.	L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
2.	L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

L-seryl-[protein]	+	ATP	=	O-phospho-L-seryl-[protein] Bound ligand (Het Group name = UN4) matches with 40.62% similarity	+	ADP	+	H(+)

L-threonyl-[protein]	+	ATP	=	O-phospho-L-threonyl-[protein] Bound ligand (Het Group name = UN4) matches with 40.62% similarity	+	ADP	+	H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/jm020056z	J Med Chem 45:3381-3393 (2002)
PubMed id: 12139449

Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O(6)-substituted guanine derivatives.
A.E.Gibson, C.E.Arris, J.Bentley, F.T.Boyle, N.J.Curtin, T.G.Davies, J.A.Endicott, B.T.Golding, S.Grant, R.J.Griffin, P.Jewsbury, L.N.Johnson, V.Mesguiche, D.R.Newell, M.E.Noble, J.A.Tucker, H.J.Whitfield.

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.

Literature references that cite this PDB file's key reference

PubMed id

Reference

20448898

F.Marchetti, C.Cano, N.J.Curtin, B.T.Golding, R.J.Griffin, K.Haggerty, D.R.Newell, R.J.Parsons, S.L.Payne, L.Z.Wang, and I.R.Hardcastle (2010).
Synthesis and biological evaluation of 5-substituted O4-alkylpyrimidines as CDK2 inhibitors.

Org Biomol Chem, 8, 2397-2407.

17085505

J.H.Alzate-Morales, R.Contreras, A.Soriano, I.Tuñon, and E.Silla (2007).
A computational study of the protein-ligand interactions in CDK2 inhibitors: using quantum mechanics/molecular mechanics interaction energy as a predictor of the biological activity.

Biophys J, 92, 430-439.

16374623

A.T.García-Sosa, and R.L.Mancera (2006).
The effect of a tightly bound water molecule on scaffold diversity in the computer-aided de novo ligand design of CDK2 inhibitors.

J Mol Model, 12, 422-431.

16374872

J.Bonet, G.Caltabiano, A.K.Khan, M.A.Johnston, C.Corbí, A.Gómez, X.Rovira, J.Teyra, and J.Villà-Freixa (2006).
The role of residue stability in transient protein-protein interactions involved in enzymatic phosphate hydrolysis. A computational study.

Proteins, 63, 65-77.

16584130

J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.

AAPS J, 8, E204-E221.

16575928

P.Dobes, M.Otyepka, M.Strnad, and P.Hobza (2006).
Interaction energies for the purine inhibitor roscovitine with cyclin-dependent kinase 2: correlated ab initio quantum-chemical, DFT and empirical calculations.

Chemistry, 12, 4297-4304.

15993080

L.Havlicek, K.Fuksova, V.Krystof, M.Orsag, B.Vojtesek, and M.Strnad (2005).
8-Azapurines as new inhibitors of cyclin-dependent kinases.

Bioorg Med Chem, 13, 5399-5407.

15723259

M.L.Fishel, M.P.Gamcsik, S.M.Delaney, E.G.Zuhowski, V.M.Maher, T.Karrison, R.C.Moschel, M.J.Egorin, and M.E.Dolan (2005).
Role of glutathione and nucleotide excision repair in modulation of cisplatin activity with O6-benzylguanine.

Cancer Chemother Pharmacol, 55, 333-342.

12244298

T.G.Davies, J.Bentley, C.E.Arris, F.T.Boyle, N.J.Curtin, J.A.Endicott, A.E.Gibson, B.T.Golding, R.J.Griffin, I.R.Hardcastle, P.Jewsbury, L.N.Johnson, V.Mesguiche, D.R.Newell, M.E.Noble, J.A.Tucker, L.Wang, and H.J.Whitfield (2002).
Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor.

Nat Struct Biol, 9, 745-749.

PDB codes:

1h1p 1h1q 1h1r 1h1s

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