期刊
NATURE CHEMICAL BIOLOGY
卷 15, 期 6, 页码 565-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41589-019-0271-0
关键词
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资金
- DOE Office of Biological and Environmental Research [KP1605010]
- NIH [R35 GM118062, R01 EB022376, R35 GM119437, R56 DK106200, R01GM105404, S10OD018483, P41GM111244]
- Howard Hughes Medical Institute
- Fonds de Recherche en Sante du Quebec
- Alfred Bader Fund
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.
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