Structural basis for Chk1 inhibition by UCN-01.
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.
Zhao
Baoguang
B
Department of Structural Biology, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.
Bower
Michael J
MJ
McDevitt
Patrick J
PJ
Zhao
Huizhen
H
Davis
Stephen T
ST
Johanson
Kyung O
KO
Green
Susan M
SM
Concha
Nestor O
NO
Zhou
Bin-Bing S
BB
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
D000470:Alkaloids; D047428:Protein Kinase Inhibitors; C054852:7-hydroxystaurosporine; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; D019311:Staurosporine