title: Structural basis for Chk1 inhibition by UCN-01.
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.
authors.affiliation: Department of Structural Biology, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.
authors.forename: Baoguang
authors.initials: B
authors.lastname: Zhao
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bower
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McDevitt
authors.forename: Huizhen
authors.initials: H
authors.lastname: Zhao
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Davis
authors.forename: Kyung O
authors.initials: KO
authors.lastname: Johanson
authors.forename: Susan M
authors.initials: SM
authors.lastname: Green
authors.forename: Nestor O
authors.initials: NO
authors.lastname: Concha
authors.forename: Bin-Bing S
authors.initials: BB
authors.lastname: Zhou
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000071877:Checkpoint Kinase 1; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000737:chemistry; D019311:Staurosporine / Q000031:analogs & derivatives; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D047428:Protein Kinase Inhibitors; C054852:7-hydroxystaurosporine; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; D019311:Staurosporine