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What Makes a Kinase Promiscuous for Inhibitors?
- Source :
-
Cell chemical biology [Cell Chem Biol] 2019 Mar 21; Vol. 26 (3), pp. 390-399.e5. Date of Electronic Publication: 2019 Jan 03. - Publication Year :
- 2019
-
Abstract
- ATP-competitive kinase inhibitors often bind several kinases due to the high conservation of the ATP binding pocket. Through clustering analysis of a large kinome profiling dataset, we found a cluster of eight promiscuous kinases that on average bind more than five times more kinase inhibitors than the other 398 kinases in the dataset. To understand the structural basis of promiscuous inhibitor binding, we determined the co-crystal structure of the receptor tyrosine kinase DDR1 with the type I inhibitors dasatinib and VX-680. Surprisingly, we find that DDR1 binds these type I inhibitors in an inactive conformation typically reserved for type II inhibitors. Our computational and biochemical studies show that DDR1 is unusually stable in this inactive conformation, giving a mechanistic explanation for inhibitor promiscuity. This phenotypic clustering analysis provides a strategy to obtain functional insights not available by sequence comparison alone.<br /> (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Subjects :
- Amino Acid Sequence
Binding Sites
Cluster Analysis
Dasatinib chemistry
Dasatinib metabolism
Discoidin Domain Receptor 1 genetics
Discoidin Domain Receptor 1 metabolism
Humans
Molecular Dynamics Simulation
Mutagenesis
Piperazines chemistry
Piperazines metabolism
Protein Binding
Protein Kinase Inhibitors metabolism
Protein Kinases chemistry
Protein Kinases metabolism
Protein Structure, Tertiary
Sequence Alignment
Discoidin Domain Receptor 1 antagonists & inhibitors
Protein Kinase Inhibitors chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 2451-9448
- Volume :
- 26
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cell chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 30612951
- Full Text :
- https://doi.org/10.1016/j.chembiol.2018.11.005