6bf9

Cryo-EM structure of human insulin degrading enzyme in complex with FAB H11-E heavy chain, FAB H11-E light chainCryo-EM structure of human insulin degrading enzyme in complex with FAB H11-E heavy chain, FAB H11-E light chain

6bf9, resolution 7.20Å Show:Asymmetric Unit Biological Assembly Structural highlights 6bf9 is a 6 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 7.2Å Experimental data: Check Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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) plays key roles in degrading peptides vital in type 2 diabetes, Alzheimer's, inflammation, and other human diseases. However, the process through which IDE recognizes peptides that tend to form amyloid fibrils remained unsolved. We used cryoEM to understand both the apo- and insulin-bound dimeric IDE states, revealing that IDE displays a large opening between the homologous ~55 kDa N- and C-terminal halves to allow selective substrate capture based on size and charge complementarity. We also used cryoEM, X-ray crystallography, SAXS, and HDX-MS to elucidate the molecular basis of how amyloidogenic peptides stabilize the disordered IDE catalytic cleft, thereby inducing selective degradation by substrate-assisted catalysis. Furthermore, our insulin-bound IDE structures explain how IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds. Together, our studies provide a mechanism for how IDE selectively degrades amyloidogenic peptides and offers structural insights for developing IDE-based therapies. Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme.,Zhang Z, Liang WG, Bailey LJ, Tan YZ, Wei H, Wang A, Farcasanu M, Woods VA, McCord LA, Lee D, Shang W, Deprez-Poulain R, Deprez B, Liu DR, Koide A, Koide S, Kossiakoff AA, Li S, Carragher B, Potter CS, Tang WJ Elife. 2018 Mar 29;7. pii: 33572. doi: 10.7554/eLife.33572. PMID:29596046 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Insulin-degrading enzyme 3D structures