Structural mapping of N676K. Structure of the autoinhibited FLT3 kinase (Protein Data Bank accession number 1RJB) is shown as a ribbon model with highlighted secondary structure and color-coded domains. N676 forms hydrogen bonds to the backbone of H671, stabilizing a loop at the back of the substrate and inhibitor-binding pocket (asterisk). N676K will remove these hydrogen bonds, likely destabilizing the loop and the nearby substrate-binding pocket. This structural effect can explain resistance against TKIs, which target the nearby pocket. However, the mutation could also lift the autoinhibition of FLT3, providing a possible explanation for the observation that this mutation alone shows transforming potential.