Chemical rescue of a mutant enzyme in living cells

Science
Yingfeng QiaoP A Cole

Abstract

The restoration of catalytic activity to mutant enzymes by small molecules is well established for in vitro systems. Here, we show that the protein tyrosine kinase Src arginine-388-->alanine (R388A) mutant can be rescued in live cells with the use of the small molecule imidazole. Cellular rescue of a viral Src homolog was rapid and reversible and conferred predicted oncogenic properties. Using chemical rescue in combination with mass spectrometry, we confirmed six known Src kinase substrates and identified several new protein targets. Chemical rescue data suggest that cellular Src is active under basal conditions. Rescue of R388A cellular Src provided insights into the mitogen-activated protein kinase pathway. This chemical rescue approach will likely have many applications in cell signaling.

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Citations

Jul 2, 2009·Journal of Chemical Biology·Anthony C Bishop, Vincent L Chen
Dec 5, 2008·Bioconjugate Chemistry·Anouk Dirksen, Philip E Dawson
Mar 6, 2009·Biochemistry·Kathryn E MuratorePhilip A Cole
Jul 5, 2012·Journal of the American Chemical Society·Eyal ArbelyJason W Chin
Jun 29, 2010·Nature Biotechnology·Andrei V KarginovKlaus M Hahn
May 13, 2010·Nature Reviews. Molecular Cell Biology·Chunaram Choudhary, Matthias Mann
Nov 22, 2011·Nature Structural & Molecular Biology·Zhihong WangPhilip A Cole
Jun 4, 2010·Nature Structural & Molecular Biology·Rong HuangPhilip A Cole
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Aug 20, 2011·Proceedings of the National Academy of Sciences of the United States of America·Adam L GarskeKevan M Shokat
Nov 28, 2012·Proceedings of the National Academy of Sciences of the United States of America·Benjamin LinAndre Levchenko
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