4IFH

Crystal structure of human insulin degrading enzyme (IDE) in complex with compound BDM44619

Replaces:  4GSE

Summary for 4IFH

• Entry DOI: 10.2210/pdb4ifh/pdb
• Descriptor: Insulin-degrading enzyme, ZINC ION, N-({1-[(2R)-4-(hydroxyamino)-1-(naphthalen-2-yl)-4-oxobutan-2-yl]-1H-1,2,3-triazol-4-yl}methyl)-4-methylbenzamide, ... (4 entities in total)
• Functional Keywords: insulin degrading enzyme, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P14735
• Total number of polymer chains: 2
• Total formula weight: 229697.44

Authors

Liang, W.G.,Guo, Q.,Deprez, R.,Deprez, B.,Tang, W. (deposition date: 2012-12-14, release date: 2013-12-18, Last modification date: 2024-02-28)

Primary citation

Deprez-Poulain, R.,Hennuyer, N.,Bosc, D.,Liang, W.G.,Enee, E.,Marechal, X.,Charton, J.,Totobenazara, J.,Berte, G.,Jahklal, J.,Verdelet, T.,Dumont, J.,Dassonneville, S.,Woitrain, E.,Gauriot, M.,Paquet, C.,Duplan, I.,Hermant, P.,Cantrelle, F.X.,Sevin, E.,Culot, M.,Landry, V.,Herledan, A.,Piveteau, C.,Lippens, G.,Leroux, F.,Tang, W.J.,van Endert, P.,Staels, B.,Deprez, B.
Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice.
Nat Commun, 6:8250-8250, 2015

PubMed Abstract: Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other bioactive peptides such as amyloid-β. Knockout and genetic studies have linked IDE to Alzheimer's disease and type-2 diabetes. As the major insulin-degrading protease, IDE is a candidate drug target in diabetes. Here we have used kinetic target-guided synthesis to design the first catalytic site inhibitor of IDE suitable for in vivo studies (BDM44768). Crystallographic and small angle X-ray scattering analyses show that it locks IDE in a closed conformation. Among a panel of metalloproteases, BDM44768 selectively inhibits IDE. Acute treatment of mice with BDM44768 increases insulin signalling and surprisingly impairs glucose tolerance in an IDE-dependent manner. These results confirm that IDE is involved in pathways that modulate short-term glucose homeostasis, but casts doubt on the general usefulness of the inhibition of IDE catalytic activity to treat diabetes.

PubMed: 26394692
DOI: 10.1038/ncomms9250

Experimental method

X-RAY DIFFRACTION (3.286 Å)