Structural differences between small gatekeeper ATP binding sites and large gatekeeper ATP binding sites.

Structural differences form the basis for BKIs to selectively act on the Giardia kinases described in this study. (a) The ATP binding pocket of protein kinases typically contains a large amino acid gatekeeper residue (e.g. methionine). (b) BKIs do not bind to the ATP binding site of typical kinases because of a clash between the “bump” and the side chain of the gatekeeper. (c) A small amino acid in the gatekeeper position has no implications for ATP access to the ATP binding site. (d) In contrast, the small gatekeeper residue permits the BKI “bump” to extend into the hydrophobic subpocket and outcompete ATP.