The 1.7 A crystal structure of human cell cycle checkpoint kinase Chk1: implications for Chk1 regulation.
The checkpoint kinase Chk1 is an important mediator of cell cycle arrest following DNA damage. The 1.7 A resolution crystal structures of the human Chk1 kinase domain and its binary complex with an ATP analog has revealed an identical open kinase conformation. The secondary structure and side chain interactions stabilize the activation loop of Chk1 and enable kinase activity without phosphorylation of the catalytic domain. Molecular modeling of the interaction of a Cdc25C peptide with Chk1 has uncovered several conserved residues that are important for substrate selectivity. In addition, we found that the less conserved C-terminal region negatively impacts Chk1 kinase activity.
Chen
P
P
Agouron Pharmaceuticals, Inc. San Diego, California 92121, USA. ping.chen@agouron.com
Luo
C
C
Deng
Y
Y
Ryan
K
K
Register
J
J
Margosiak
S
S
Tempczyk-Russell
A
A
Nguyen
B
B
Myers
P
P
Lundgren
K
K
Kan
C C
CC
O'Connor
P M
PM
D020134:Catalytic Domain; D002453:Cell Cycle / Q000502:physiology*; D000071877:Checkpoint Kinase 1; D017124:Conserved Sequence; D003461:Crystallography; D004789:Enzyme Activation / Q000502:physiology; D005057:Eukaryotic Cells / Q000166:cytology / Q000201:enzymology; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1