5VD0

CRYSTAL STRUCTURE OF HUMAN MYT1 KINASE DOMAIN IN COMPLEX WITH MK1775

5VD0 の概要

• エントリーDOI: 10.2210/pdb5vd0/pdb
• 関連するPDBエントリー: 5VCW 5VCX 5VCY 5VCZ 5VD1 5VD3
• 分子名称: Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase, 1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-2-(prop-2-en-1-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, DI(HYDROXYETHYL)ETHER, ... (4 entities in total)
• 機能のキーワード: kinase domain, cell cycle, tyrosine- and threonine-specific kinase, membrane-associated protein kinase, transferase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35104.85

構造登録者

Zhu, J.-Y.,Schonbrunn, E. (登録日: 2017-04-01, 公開日: 2017-08-23, 最終更新日: 2024-03-06)

主引用文献

Zhu, J.Y.,Cuellar, R.A.,Berndt, N.,Lee, H.E.,Olesen, S.H.,Martin, M.P.,Jensen, J.T.,Georg, G.I.,Schonbrunn, E.
Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors.
J. Med. Chem., 60:7863-7875, 2017

PubMed Abstract: Members of the Wee family of kinases negatively regulate the cell cycle via phosphorylation of CDK1 and are considered potential drug targets. Herein, we investigated the structure-function relationship of human Wee1, Wee2, and Myt1 (PKMYT1). Purified recombinant full-length proteins and kinase domain constructs differed substantially in phosphorylation states and catalytic competency, suggesting complex mechanisms of activation. A series of crystal structures reveal unique features that distinguish Wee1 and Wee2 from Myt1 and establish the structural basis of differential inhibition by the widely used Wee1 inhibitor MK-1775. Kinome profiling and cellular studies demonstrate that, in addition to Wee1 and Wee2, MK-1775 is an equally potent inhibitor of the polo-like kinase PLK1. Several previously unrecognized inhibitors of Wee kinases were discovered and characterized. Combined, the data provide a comprehensive view on the catalytic and structural properties of Wee kinases and a framework for the rational design of novel inhibitors thereof.

PubMed: 28792760
DOI: 10.1021/acs.jmedchem.7b00996

実験手法

X-RAY DIFFRACTION (2.13 Å)