PDBsum entry 2w0j

Transferase

PDB id: 2w0j

Contents

Protein chain

280 a.a. *

Ligands

ZAT

NO3

Waters ×133

* Residue conservation analysis

PDB id:

2w0j

Name:

Transferase

Title:

Crystal structure of chk2 in complex with nsc 109555, a specific inhibitor

Structure:

Serine/threonine-protein kinase chk2. Chain: a. Fragment: catalytic domain, residues 210-531. Synonym: checkpoint kinase 2, cds1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.05Å R-factor: 0.217 R-free: 0.246

Authors:

G.T.Lountos,J.E.Tropea,D.Zhang,A.G.Jobson,Y.Pommier,R.H.Shoemaker, D.S.Waugh

Key ref:

G.T.Lountos et al. (2009). Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor. Protein Sci, 18, 92-100. PubMed id: 19177354 DOI: 10.1002/pro.16

Date:

18-Aug-08 Release date: 10-Feb-09

Protein chain

O96017  (CHK2_HUMAN) -  Serine/threonine-protein kinase Chk2 from Homo sapiens

Seq: 543 a.a.

Struc: 280 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine protein 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: 10.1002/pro.16

Protein Sci 18:92-100 (2009)

PubMed id: 19177354

Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor.

G.T.Lountos, J.E.Tropea, D.Zhang, A.G.Jobson, Y.Pommier, R.H.Shoemaker, D.S.Waugh.

ABSTRACT

Checkpoint kinase 2 (Chk2), a ser/thr kinase involved in the ATM-Chk2 checkpoint pathway, is activated by genomic instability and DNA damage and results in either arrest of the cell cycle to allow DNA repair to occur or apoptosis if the DNA damage is severe. Drugs that specifically target Chk2 could be beneficial when administered in combination with current DNA-damaging agents used in cancer therapy. Recently, a novel inhibitor of Chk2, NSC 109555, was identified that exhibited high potency (IC(50) = 240 nM) and selectivity. This compound represents a new chemotype and lead for the development of novel Chk2 inhibitors that could be used as therapeutic agents for the treatment of cancer. To facilitate the discovery of new analogs of NSC 109555 with even greater potency and selectivity, we have solved the crystal structure of this inhibitor in complex with the catalytic domain of Chk2. The structure confirms that the compound is an ATP-competitive inhibitor, as the electron density clearly reveals that it occupies the ATP-binding pocket. However, the mode of inhibition differs from that of the previously studied structure of Chk2 in complex with debromohymenialdisine, a compound that inhibits both Chk1 and Chk2. A unique hydrophobic pocket in Chk2, located very close to the bound inhibitor, presents an opportunity for the rational design of compounds with higher binding affinity and greater selectivity.

Selected figure(s)

Figure 1.
A: Chemical structure of NSC 109555. B: The coordinates of NSC 109555 superimposed on the final 2F[o] [minus sign] F[c] electron density maps at 2.05 A resolution contoured at the 1[sigma] level.

Figure 5.
An overlay of the coordinates of the Chk2-NSC 109555 (PDB code: 2W0J), Chk2-ADP (PDB code: 2CN5), and Chk2-DBQ (PDB code: 2CN8) crystal structures comparing the orientations of NSC 109555 (blue stick), ADP (orange stick), and DBQ (purple stick) in the ATP-binding pocket of Chk2 (green stick). The coordinates for the amino acid side chains are for the refined model of Chk2 in complex with NSC 109555.

The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (2009, 18, 92-100) copyright 2009.

Figures were selected by an automated process.