PDBsum entry 1oiu

Kinase

PDB id: 1oiu

Contents

Protein chains

297 a.a. *

256 a.a. *

266 a.a. *

Ligands

N76 ×2

SGM ×2

Metals

_MG

Waters ×646

* Residue conservation analysis

PDB id:

1oiu

Name:

Kinase

Title:

Structure of human thr160-phospho cdk2/cyclin a complexed with a 6- cyclohexylmethyloxy-2-anilino-purine inhibitor

Structure:

Cell division protein kinase 2. Chain: a, c. Synonym: p33 protein kinase, cdk2. Engineered: yes. Other_details: phosphorylated on thr160. Cyclin a2. Chain: b, d. Fragment: residues 174-432. Synonym: cyclin a, ccna2, ccna, ccn1.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Biol. unit:

Dimer (from PDB file)

Resolution:

2.00Å R-factor: 0.216 R-free: 0.253

Authors:

D.J.Pratt,J.A.Endicott,M.E.M.Noble

Key ref:

I.R.Hardcastle et al. (2004). N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2. J Med Chem, 47, 3710-3722. PubMed id: 15239650 DOI: 10.1021/jm0311442

Date:

26-Jun-03 Release date: 13-Jul-04

Protein chain

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

Seq: 298 a.a.

Struc: 297 a.a.*

Protein chains

P20248  (CCNA2_HUMAN) -  Cyclin-A2 from Homo sapiens

Seq: 432 a.a.

Struc: 256 a.a.

Protein chain

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

Seq: 298 a.a.

Struc: 266 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, C: E.C.2.7.11.22 - cyclin-dependent kinase.
• 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⁺

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

reference

DOI no: 10.1021/jm0311442

J Med Chem 47:3710-3722 (2004)

PubMed id: 15239650

N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2.

I.R.Hardcastle, C.E.Arris, J.Bentley, F.T.Boyle, Y.Chen, N.J.Curtin, J.A.Endicott, A.E.Gibson, B.T.Golding, R.J.Griffin, P.Jewsbury, J.Menyerol, V.Mesguiche, D.R.Newell, M.E.Noble, D.J.Pratt, L.Z.Wang, H.J.Whitfield.

ABSTRACT

The adenosine 5'-triphosphate (ATP) competitive cyclin-dependent kinase inhibitor O(6)-cyclohexylmethylguanine (NU2058, 1) has been employed as the lead in a structure-based drug discovery program resulting in the discovery of the potent CDK1 and -2 inhibitor NU6102 (3, IC(50) = 9.5 nM and 5.4 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). The SAR for this series have been explored further by the synthesis and evaluation of 45 N(2)-substituted analogues of NU2058. These studies have confirmed the requirement for the hydrogen bonding N(2)-NH group and the requirement for an aromatic N(2)-substituent to confer potency in the series. Additional potency is conferred by the presence of a group capable of donating a hydrogen bond at the 4'-position, for example, the 4'-hydroxy derivative (25, IC(50) = 94 nM and 69 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), 4'-monomethylsulfonamide derivative (28, IC(50) = 9 nM and 7.0 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), and 4'-carboxamide derivative (34, IC(50) = 67 nM and 64 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). X-ray crystal structures have been obtained for key compounds and have been used to explain the observed trends in activity.