PDBsum entry 6guh

Cell cycle

PDB id: 6guh

Contents

Protein chain

284 a.a.

Ligands

FB8

EDO ×2

Waters ×156

PDB id:

6guh

Name:

Cell cycle

Title:

Cdk2 in complex with azd5438

Structure:

Cyclin-dependent kinase 2. Chain: a. Synonym: cell division protein kinase 2,p33 protein kinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk2, cdkn2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.50Å R-factor: 0.201 R-free: 0.243

Authors:

D.J.Wood,S.Korolchuk,N.J.Tatum,L.Z.Wang,J.A.Endicott,M.E.M.Noble, M.P.Martin

Key ref:

D.J.Wood et al. (2019). Differences in the Conformational Energy Landscape of CDK1 and CDK2 Suggest a Mechanism for Achieving Selective CDK Inhibition. Cell Chem Biol, 26, 121. PubMed id: 30472117 DOI: 10.1016/j.chembiol.2018.10.015

Date:

19-Jun-18 Release date: 05-Dec-18

Protein chain

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

Seq: 298 a.a.

Struc: 284 a.a.

Enzyme reactions

• Enzyme class: 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.chembiol.2018.10.015

Cell Chem Biol 26:121 (2019)

PubMed id: 30472117

Differences in the Conformational Energy Landscape of CDK1 and CDK2 Suggest a Mechanism for Achieving Selective CDK Inhibition.

D.J.Wood, S.Korolchuk, N.J.Tatum, L.Z.Wang, J.A.Endicott, M.E.M.Noble, M.P.Martin.

ABSTRACT

Dysregulation of the cell cycle characterizes many cancer subtypes, providing a rationale for developing cyclin-dependent kinase (CDK) inhibitors. Potent CDK2 inhibitors might target certain cancers in which CCNE1 is amplified. However, current CDK2 inhibitors also inhibit CDK1, generating a toxicity liability. We have used biophysical measurements and X-ray crystallography to investigate the ATP-competitive inhibitor binding properties of cyclin-free and cyclin-bound CDK1 and CDK2. We show that these kinases can readily be distinguished by such inhibitors when cyclin-free, but not when cyclin-bound. The basis for this discrimination is unclear from either inspection or molecular dynamics simulation of ligand-bound CDKs, but is reflected in the contacts made between the kinase N- and C-lobes. We conclude that there is a subtle but profound difference between the conformational energy landscapes of cyclin-free CDK1 and CDK2. The unusual properties of CDK1 might be exploited to differentiate CDK1 from other CDKs in future cancer therapeutic design.