5WI2

Crystal structure of the KA1 domain from human Chk1

5WI2 の概要

• エントリーDOI: 10.2210/pdb5wi2/pdb
• 分子名称: cDNA FLJ56409, highly similar to Serine/threonine-protein kinase Chk1 (EC 2.7.11.1), ACETATE ION, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: kinase, checkpoint, autoinhibition, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 24336.42

構造登録者

Emptage, R.P.,Marmorstein, R. (登録日: 2017-07-18, 公開日: 2017-10-04, 最終更新日: 2024-11-06)

主引用文献

Emptage, R.P.,Schoenberger, M.J.,Ferguson, K.M.,Marmorstein, R.
Intramolecular autoinhibition of checkpoint kinase 1 is mediated by conserved basic motifs of the C-terminal kinase-associated 1 domain.
J. Biol. Chem., 292:19024-19033, 2017

PubMed Abstract: Precise control of the cell cycle allows for timely repair of genetic material prior to replication. One factor intimately involved in this process is checkpoint kinase 1 (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 point to KA1-mediated intramolecular autoinhibition as a key regulatory mechanism of human Chk1, and provide new therapeutic possibilities with which to attack this validated oncology target with small molecules.

PubMed: 28972186
DOI: 10.1074/jbc.M117.811265

実験手法

X-RAY DIFFRACTION (2.495 Å)