How ATP-Competitive Inhibitors Allosterically Modulate Tyrosine Kinases That Contain a Src-like Regulatory Architecture
| Autor: | Markus A. Seeliger, Ames C. Register, Sujata Chakraborty, Zachary E. Potter, Linglan Fang, Dustin J. Maly, Jessica Vilas-Boas |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Protein Conformation Allosteric regulation 01 natural sciences Biochemistry Article src Homology Domains 03 medical and health sciences Allosteric Regulation Catalytic Domain Humans Binding site Protein Kinase Inhibitors 010405 organic chemistry Chemistry Kinase General Medicine Small molecule 0104 chemical sciences Cell biology Atp competitive 030104 developmental biology Pyrimidines src-Family Kinases Helix Molecular Medicine Pyrazoles Tyrosine kinase Proto-oncogene tyrosine-protein kinase Src HeLa Cells Protein Binding |
| Zdroj: | ACS Chem Biol |
| ISSN: | 1554-8937 |
| Popis: | Small molecule kinase inhibitors that stabilize distinct ATP binding site conformations can differentially modulate the global conformation of Src-family kinases (SFKs). However, it is unclear which specific ATP binding site contacts are responsible for modulating the global conformation of SFKs and whether these inhibitor-mediated allosteric effects generalize to other tyrosine kinases. Here, we describe the development of chemical probes that allow us to deconvolute which features in the ATP binding site are responsible for the allosteric modulation of the global conformation of Src. We find that the ability of an inhibitor to modulate the global conformation of Src's regulatory domain-catalytic domain module relies mainly on the influence it has on the conformation of a structural element called helix αC. Furthermore, by developing a set of orthogonal probes that target a drug-sensitized Src variant, we show that stabilizing Src's helix αC in an active conformation is sufficient to promote a Src-mediated, phosphotransferase-independent alteration in cell morphology. Finally, we report that ATP-competitive, conformation-selective inhibitors can influence the global conformation of tyrosine kinases beyond the SFKs, suggesting that the allosteric networks we observe in Src are conserved in kinases that have a similar regulatory architecture. Our study highlights that an ATP-competitive inhibitor's interactions with helix αC can have a major influence on the global conformation of some tyrosine kinases. |
| Databáze: | OpenAIRE |
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