A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators

Glucokinase activators are attractive therapeutics in diabetes, but their benefits can be offset by hypoglycemia, owing to the allosteric enhancement of the enzyme's glucose affinity. The biochemical and structural dissection of the interaction between glucokinase and a phosphomimetic of the BH3 α-helix derived from human BAD, a glucokinase-binding partner, demonstrates a new binding region and distinct mode of enzyme activation.