6EDS

Structure of Cysteine-free Human Insulin-Degrading Enzyme in complex with Glucagon and Substrate-selective Macrocyclic Inhibitor 63

Summary for 6EDS

• Entry DOI: 10.2210/pdb6eds/pdb
• Related: 2G49 4LTE 6BYZ
• Descriptor: Insulin-degrading enzyme, Glucagon, {(8R,9S,10S)-9-(2',3'-dimethyl[1,1'-biphenyl]-4-yl)-6-[(1-methyl-1H-imidazol-2-yl)sulfonyl]-1,6-diazabicyclo[6.2.0]decan-10-yl}methanol, ... (6 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: 235209.98

Authors

Tan, G.A.,Seeliger, M.A.,Maianti, J.P.,Liu, D.R.,Welsh, A.J. (deposition date: 2018-08-10, release date: 2019-04-03, Last modification date: 2023-10-11)

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

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: 31086331
DOI: 10.1038/s41589-019-0271-0

Experimental method

X-RAY DIFFRACTION (3.18071730876 Å)