PDBsum entry 2uzd

Transferase

PDB id: 2uzd

Contents

Protein chains

296 a.a. *

258 a.a. *

Ligands

C85 ×2

Waters ×201

* Residue conservation analysis

PDB id:

2uzd

Name:

Transferase

Title:

Crystal structure of human cdk2 complexed with a thiazolidinone inhibitor

Structure:

Cell division protein kinase 2. Chain: a, c. Synonym: p33 protein kinase, cyclin dependent kinase 2. Engineered: yes. Other_details: thr160 phosphorylated. Cyclin a2. Chain: b, d. Fragment: 175-432. Synonym: cyclin-a.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

2.72Å R-factor: 0.211 R-free: 0.269

Authors:

C.M.Richardson,P.Dokurno,J.B.Murray,A.E.Surgenor

Key ref:

C.M.Richardson et al. (2007). Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping. Bioorg Med Chem Lett, 17, 3880-3885. PubMed id: 17570665 DOI: 10.1016/j.bmcl.2007.04.110

Date:

27-Apr-07 Release date: 26-Jun-07

Protein chains

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

Seq: 298 a.a.

Struc: 296 a.a.*

Protein chains

P20248  (CCNA2_HUMAN) -  Cyclin-A2 from Homo sapiens

Seq: 432 a.a.

Struc: 258 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

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: 10.1016/j.bmcl.2007.04.110

Bioorg Med Chem Lett 17:3880-3885 (2007)

PubMed id: 17570665

Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping.

C.M.Richardson, C.L.Nunns, D.S.Williamson, M.J.Parratt, P.Dokurno, R.Howes, J.Borgognoni, M.J.Drysdale, H.Finch, R.E.Hubbard, P.S.Jackson, P.Kierstan, G.Lentzen, J.D.Moore, J.B.Murray, H.Simmonite, A.E.Surgenor, C.J.Torrance.

ABSTRACT

Virtual screening against a pCDK2/cyclin A crystal structure led to the identification of a potent and novel CDK2 inhibitor, which exhibited an unusual mode of interaction with the kinase binding motif. With the aid of X-ray crystallography and modelling, a medicinal chemistry strategy was implemented to probe the interactions seen in the crystal structure and to establish SAR. A fragment-based approach was also considered but a different, more conventional, binding mode was observed. Compound selectivity against GSK-3beta was improved using a rational design strategy, with crystallographic verification of the CDK2 binding mode.