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

Nat Struct Mol Biol. 2014 Jan;21(1):36-42. doi: 10.1038/nsmb.2717. Epub 2013 Dec 8.


Glucokinase (GK) is a glucose-phosphorylating enzyme that regulates insulin release and hepatic metabolism, and its loss of function is implicated in diabetes pathogenesis. GK activators (GKAs) are attractive therapeutics in diabetes; however, clinical data indicate that their benefits can be offset by hypoglycemia, owing to marked allosteric enhancement of the enzyme's glucose affinity. We show that a phosphomimetic of the BCL-2 homology 3 (BH3) α-helix derived from human BAD, a GK-binding partner, increases the enzyme catalytic rate without dramatically changing glucose affinity, thus providing a new mechanism for pharmacologic activation of GK. Remarkably, BAD BH3 phosphomimetic mediates these effects by engaging a new region near the enzyme's active site. This interaction increases insulin secretion in human islets and restores the function of naturally occurring human GK mutants at the active site. Thus, BAD phosphomimetics may serve as a new class of GKAs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Animals
  • Enzyme Activation
  • Glucokinase / metabolism*
  • Humans
  • Phosphoproteins / physiology*


  • Phosphoproteins
  • Glucokinase