6BFC

Cryo-EM structure of human insulin degrading enzyme in complex with insulin

Summary for 6BFC

• Entry DOI: 10.2210/pdb6bfc/pdb
• Related: 6B3Q
• EMDB information: 7041
• Descriptor: Insulin-degrading enzyme, Insulin (2 entities in total)
• Functional Keywords: ide, amyloid beta, hormone, hydrolase-hormone complex, hydrolase/hormone
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 247712.69

Authors

Liang, W.G.,Zhang, Z.,Bailey, L.J.,Kossiakoff, A.A.,Tan, Y.Z.,Wei, H.,Carragher, B.,Potter, S.C.,Tang, W.J. (deposition date: 2017-10-26, release date: 2017-12-27, Last modification date: 2021-04-28)

Primary citation

Zhang, Z.,Liang, W.G.,Bailey, L.J.,Tan, Y.Z.,Wei, H.,Wang, A.,Farcasanu, M.,Woods, V.A.,McCord, L.A.,Lee, D.,Shang, W.,Deprez-Poulain, R.,Deprez, B.,Liu, D.R.,Koide, A.,Koide, S.,Kossiakoff, A.A.,Li, S.,Carragher, B.,Potter, C.S.,Tang, W.J.
Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme.
Elife, 7:-, 2018

PubMed Abstract: Insulin degrading enzyme (IDE) plays key roles in degrading peptides vital in type two 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.

PubMed: 29596046
DOI: 10.7554/eLife.33572

Experimental method

ELECTRON MICROSCOPY (3.7 Å)