|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Maianti, JPablo, Tan, GA, Vetere, A, Welsh, AJ, Wagner, BK, Seeliger, MA, Liu, DR|
|Journal||Nat Chem Biol|
|Date Published||2019 May 13|
Enzymes that act on multiple substrates are common in biology but pose unique challenges as therapeutic targets. The metalloprotease insulin-degrading enzyme (IDE) modulates blood glucose levels by cleaving insulin, a hormone that promotes glucose clearance. However, IDE also degrades glucagon, a hormone that elevates glucose levels and opposes the effect of insulin. IDE inhibitors to treat diabetes, therefore, should prevent IDE-mediated insulin degradation, but not glucagon degradation, in contrast with traditional modes of enzyme inhibition. Using a high-throughput screen for non-active-site ligands, we discovered potent and highly specific small-molecule inhibitors that alter IDE's substrate selectivity. X-ray co-crystal structures, including an IDE-ligand-glucagon ternary complex, revealed substrate-dependent interactions that enable these inhibitors to potently block insulin binding while allowing glucagon cleavage, even at saturating inhibitor concentrations. These findings suggest a path for developing IDE-targeting therapeutics, and offer a blueprint for modulating other enzymes in a substrate-selective manner to unlock their therapeutic potential.
|Alternate Journal||Nat. Chem. Biol.|