5VCX

CRYSTAL STRUCTURE OF HUMAN MYT1 KINASE DOMAIN (UNTREATED) IN COMPLEX WITH SARACATINIB

Summary for 5VCX

• Entry DOI: 10.2210/pdb5vcx/pdb
• Related: 5VCV 5VCW 5VCY 5VCZ 5VD0 5VD1 5VD3
• Descriptor: Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase, N-(5-CHLORO-1,3-BENZODIOXOL-4-YL)-7-[2-(4-METHYLPIPERAZIN-1-YL)ETHOXY]-5-(TETRAHYDRO-2H-PYRAN-4-YLOXY)QUINAZOLIN-4-AMINE, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: kinase domain, cell cycle, tyrosine- and threonine-specific kinase, membrane-associated protein kinase, transferase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 35102.23

Authors

Zhu, J.-Y.,Schonbrunn, E. (deposition date: 2017-04-01, release date: 2017-08-23, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.7 Å)