4re9 | pdb_00004re9

Crystal structure of human insulin degrading enzyme (IDE) in complex with compound 71290

spinqualitylabelsall models 4re9, resolution 2.91Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4re9 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 1PE, 3M9, EDO, EPE, PEG, ZN Activity: Insulysin, with EC number 3.4.24.56 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum Function [IDE_HUMAN] Plays a role in the cellular breakdown of insulin, IAPP, glucagon, bradykinin, kallidin and other peptides, and thereby plays a role in intercellular peptide signaling. Degrades amyloid formed by APP and IAPP. May play a role in the degradation and clearance of naturally secreted amyloid beta-protein by neurons and microglia. Publication Abstract from PubMed Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other bioactive peptides such as amyloid-beta. 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. Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice.,Deprez-Poulain R, Hennuyer N, Bosc D, Liang WG, 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 FX, Sevin E, Culot M, Landry V, Herledan A, Piveteau C, Lippens G, Leroux F, Tang WJ, van Endert P, Staels B, Deprez B Nat Commun. 2015 Sep 23;6:8250. doi: 10.1038/ncomms9250. PMID:26394692 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA