Substitution of the active site gatekeeper residue in the BCR-ABL oncoprotein and related kinases is a common mechanism of imanitib resistance but has also been observed in drug-naïve patients. New work suggests that this residue stabilizes a hydrophobic spine that links the N and C kinase lobes, promoting the active conformation, and that adverse mutations at the gatekeeper residue further stabilize the spine. Disruption of the spine would be an attractive new goal in drug development.
- Mohammad Azam
- Markus A Seeliger
- George Q Daley
