5wi2

Publication Abstract from PubMed

Precise control of the cell cycle allows for timely repair of genetic material prior to replication. One factor intimately involved in this process is Chk1, a DNA damage repair inducing Ser/Thr protein kinase that contains an N-terminal kinase domain and a C-terminal regulatory region consisting of a ~100-residue linker followed by a putative kinase associated-1 (KA1) domain. We report the crystal structure of the human Chk1 KA1 domain, demonstrating striking structural homology with other sequentially diverse KA1 domains. Separately purified Chk1 kinase and KA1 domains are intimately associated in solution, which results in inhibition of Chk1 kinase activity. Using truncation mutants and site-directed mutagenesis, we define the inhibitory face of the KA1 domain as a series of basic residues residing on two conserved regions of the primary structure. These findings define the molecular basis for KA1- mediated intramolecular autoinhibition as a key regulatory mechanism of human Chk1, and provides new therapeutic possibilities with which to attack this validated oncology target with small-molecules.

Intramolecular autoinhibition of Checkpoint Kinase 1 is mediated by conserved basic motifs of the C-terminal Kinase Associated-1 domain.,Emptage RP, Schoenberger MJ, Ferguson KM, Marmorstein R J Biol Chem. 2017 Sep 25. pii: jbc.M117.811265. doi: 10.1074/jbc.M117.811265. PMID:28972186^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.