Gatekeeper mutations

In addition to a direct effect on the shape and character of the binding pocket, recent mutagenesis suggests that gatekeeper mutations in several... 

Adenomatous polyposis coli (APC) gene A tumor suppressor gene, acting as a gatekeeper to prevent development of tumors. A familial cancer syndrome called FAP, or familial adenomatous polyposis, is caused by mutations in APC. Mutation of APC also occurs commonly in sporadic cases of colorectal carcinoma. 

Figure 4 Protein kinases with the "gatekeeper" residue mutated to glycine that makes them recognize N -substituted ATP analogs also programs them to be uniquely sensitive to designed inhibitors, allowing rapid generation of potent selective kinase inhibitors of any protein kinase.

A crystal structure of the mutant T790M kinase is available that shows the new gatekeeper methionine able to move to accommodate a bound inhibitor. This is consistent with the observed binding of inhibitors to mutant and double mutant kinases containing this mutation.74... 

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