Download MendeleyStructural Basis for Chk1 Inhibition by UCN-01
Zhao, B., Bower, M.J., McDevitt, P.J., Zhao, H., Davis, S.T., Johanson, K.O., Green, S.M., Concha, N.O., Zhou, B.B.(2002) J Biol Chem 277: 46609-46615
- PubMed: 12244092
- DOI: https://doi.org/10.1074/jbc.M201233200
- Primary Citation of Related Structures:
1NVQ, 1NVR, 1NVS - PubMed 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.
Organizational Affiliation:
Department of Structural Biology, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.
