Saturday, September 17, 2011

Chemical genetic strategy for targeting protein kinases based on covalent complementarity

Previous work has showed that enlarging the binding pocket of some conserved proteins such as protein kinases and adding an allel specific (AS) inhibitor can help elucidate their function. However, using this method (bump and hole method) can reduce the efficiency of the protein of interest. In this current article, Shokat addresses these problems and comes up with a new strategy. In previous works, Shokat enlarged the binding pocket by changing a large hydrophobic residue to a glycine or alanine, but in this current work, he changes the residue to a cysteine. He believes that by changing the residue to a cysteine, the structure of the conserved binding pocket will be conserved, and the protein, which is called an electrophilesensitive (ES) allele, can be targeted by a electrophilic inhibitor. (See figure)

2 comments:

  1. That is a good example of "this is so simple, I wish I would have thought of this". Great stuff!

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  2. I also noticed that in this paper and all of his other papers he never calls the method bump and hole. He calls it allel specific inhibition. I wonder how the name bump and hole came to be and why no one else uses allel specific inhibition.

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