6BYZ
Structure of Cysteine-free Human Insulin-Degrading Enzyme in complex with Substrate-selective Macrocyclic Inhibitor 37
Summary for 6BYZ
| Entry DOI | 10.2210/pdb6byz/pdb |
| Descriptor | Insulin-degrading enzyme, ALA-ALA-ALA, [(8R,9S,10S)-9-(2',3'-dimethyl[1,1'-biphenyl]-4-yl)-6-{[2-(trifluoromethyl)phenyl]sulfonyl}-1,6-diazabicyclo[6.2.0]decan-10-yl]methanol, ... (5 entities in total) |
| Functional Keywords | insulin, glucagon, diabetes, exo-site, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 237993.75 |
| Authors | Tan, G.A.,Seeliger, M.A.,Maianti, J.P.,Liu, D.R. (deposition date: 2017-12-21, release date: 2019-04-03, Last modification date: 2023-10-04) |
| Primary citation | Maianti, J.P.,Tan, G.A.,Vetere, A.,Welsh, A.J.,Wagner, B.K.,Seeliger, M.A.,Liu, D.R. Substrate-selective inhibitors that reprogram the activity of insulin-degrading enzyme. Nat.Chem.Biol., 15:565-574, 2019 Cited by PubMed Abstract: 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. PubMed: 31086331DOI: 10.1038/s41589-019-0271-0 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.95624845742 Å) |
Structure validation
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