PDBsum entry 2iw8

Cell cycle

PDB id: 2iw8

Contents

Protein chains

298 a.a. *

255 a.a. *

266 a.a. *

Ligands

4SP ×2

SGM ×2

Waters ×309

* Residue conservation analysis

PDB id:

2iw8

Name:

Cell cycle

Title:

Structure of human thr160-phospho cdk2-cyclin a f82h-l83v-h84d mutant with an o6-cyclohexylmethylguanine inhibitor

Structure:

Cell division protein kinase 2. Chain: a, c. Synonym: cyclin dependent kinase 2, p33 protein kinase. Engineered: yes. Mutation: yes. Other_details: phosphothreonine 160. Cyclin-a2. Chain: b, d. Fragment: a3, residues 174-432.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Other_details: wild type gene was a gift from dr d.O.Morgan. Other_details: full length cyclin a was a gift from dr m.Doree

Biol. unit:

Tetramer (from PDB file)

Resolution:

2.30Å R-factor: 0.214 R-free: 0.255

Authors:

D.J.Pratt,J.Bentley,P.Jewsbury,F.T.Boyle,J.A.Endicott,M.E.M.Noble

Key ref:

D.J.Pratt et al. (2006). Dissecting the determinants of cyclin-dependent kinase 2 and cyclin-dependent kinase 4 inhibitor selectivity. J Med Chem, 49, 5470-5477. PubMed id: 16942020 DOI: 10.1021/jm060216x

Date:

27-Jun-06 Release date: 06-Sep-06

Protein chain

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

Seq: 298 a.a.

Struc: 298 a.a.*

Protein chains

P20248  (CCNA2_HUMAN) -  Cyclin-A2 from Homo sapiens

Seq: 432 a.a.

Struc: 255 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 8 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/jm060216x

J Med Chem 49:5470-5477 (2006)

PubMed id: 16942020

Dissecting the determinants of cyclin-dependent kinase 2 and cyclin-dependent kinase 4 inhibitor selectivity.

D.J.Pratt, J.Bentley, P.Jewsbury, F.T.Boyle, J.A.Endicott, M.E.Noble.

ABSTRACT

Cyclin dependent kinases are a key family of kinases involved in cell cycle regulation and are an attractive target for cancer chemotherapy. The roles of four residues of the cyclin-dependent kinase active site in inhibitor selectivity were investigated by producing cyclin-dependent kinase 2 mutants bearing equivalent cyclin-dependent kinase 4 residues, namely F82H, L83V, H84D, and K89T. Assay of the mutants with a cyclin-dependent kinase 4-selective bisanilinopyrimidine shows that the K89T mutation is primarily responsible for the selectivity of this compound. Use of the cyclin-dependent kinase 2-selective 6-cyclohexylmethoxy-2-(4'-sulfamoylanilino)purine (NU6102) shows that K89T has no role in the selectivity, while the remaining three mutations have a cumulative influence. The results indicate that certain residues that are not frequently considered in structure-aided kinase inhibitor design have an important role to play.