| Autor: |
Maianti JP; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA.; Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Tan GA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA., Vetere A; Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Welsh AJ; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA., Wagner BK; Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Seeliger MA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA. markus.seeliger@stonybrook.edu., Liu DR; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA. drliu@fas.harvard.edu.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. drliu@fas.harvard.edu.; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA. drliu@fas.harvard.edu.; Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA, USA. drliu@fas.harvard.edu. |
| Abstrakt: |
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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