PDBsum entry 1nvq

Transferase

PDB id: 1nvq

Contents

Protein chain

264 a.a. *

Ligands

ALA-SER-VAL-SER-ALA

SO4

UCN

Waters ×192

* Residue conservation analysis

PDB id:

1nvq

Name:

Transferase

Title:

The complex structure of checkpoint kinase chk1/ucn-01

Structure:

Serine/threonine-protein kinase chk1. Chain: a. Fragment: chk1kd (residues 1-289). Engineered: yes. Peptide asvsa. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469. Synthetic: yes

Biol. unit:

Dimer (from PQS)

Resolution:

2.00Å R-factor: 0.206 R-free: 0.234

Authors:

B.Zhao,M.J.Bower,P.J.Mcdevitt,H.Zhao,S.T.Davis,K.O.Johanson, S.M.Green,N.O.Concha,B.B.Zhou

Key ref:

B.Zhao et al. (2002). Structural basis for Chk1 inhibition by UCN-01. J Biol Chem, 277, 46609-46615. PubMed id: 12244092 DOI: 10.1074/jbc.M201233200

Date:

04-Feb-03 Release date: 08-Apr-03

Protein chain

O14757  (CHK1_HUMAN) -  Serine/threonine-protein kinase Chk1 from Homo sapiens

Seq: 476 a.a.

Struc: 264 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: 10.1074/jbc.M201233200

J Biol Chem 277:46609-46615 (2002)

PubMed id: 12244092

Structural basis for Chk1 inhibition by UCN-01.

B.Zhao, M.J.Bower, P.J.McDevitt, H.Zhao, S.T.Davis, K.O.Johanson, S.M.Green, N.O.Concha, B.B.Zhou.

ABSTRACT

Chk1 is a serine-threonine kinase that plays an important role in the DNA damage response, including G(2)/M cell cycle control. UCN-01 (7-hydroxystaurosporine), currently in clinical trials, has recently been shown to be a potent Chk1 inhibitor that abrogates the G(2)/M checkpoint induced by DNA-damaging agents. To understand the structural basis of Chk1 inhibition by UCN-01, we determined the crystal structure of the Chk1 kinase domain in complex with UCN-01. Chk1 structures with staurosporine and its analog SB-218078 were also determined. All three compounds bind in the ATP-binding pocket of Chk1, producing only slight changes in the protein conformation. Selectivity of UCN-01 toward Chk1 over cyclin-dependent kinases can be explained by the presence of a hydroxyl group in the lactam moiety interacting with the ATP-binding pocket. Hydrophobic interactions and hydrogen-bonding interactions were observed in the structures between UCN-01 and the Chk1 kinase domain. The high structural complementarity of these interactions is consistent with the potency and selectivity of UCN-01.

Selected figure(s)

Figure 1.
Fig. 1. A ribbon diagram of the Chk1 kinase domain in complex with UCN-01. The N-terminal domain is in green, the C-terminal domain is in yellow, and the activation loop is in magenta. Elements of secondary structure are numbered from the N to the C termini accordingly. UCN-01 is shown in a ball-and-stick presentation: red for oxygen atoms, blue for nitrogen, and yellow for carbon. All figures were created with the computer programs MolScript (25) and BobScript (26).

Figure 5.
Fig. 5. The solvent-accessible surface of the bound conformation of UCN-01 (purple) is shown with the solvent-accessible surface of Chk1 (green mesh) in the Chk1·UCN-01 complex. The shape complementarity between this rigid inhibitor and the binding site is very high, and the large amount of non-polar buried surface area in the complex provides the energy for a very strong interaction.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2002, 277, 46609-46615) copyright 2002.

Figures were selected by an automated process.