3QZ2

The structure of cysteine-free human insulin degrading enzyme

Summary for 3QZ2

• Entry DOI: 10.2210/pdb3qz2/pdb
• Descriptor: Insulin-degrading enzyme, ZINC ION (3 entities in total)
• Functional Keywords: insulin degrading enzyme, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P14735
• Total number of polymer chains: 2
• Total formula weight: 229253.94

Authors

Guo, Q.,Tang, W.J. (deposition date: 2011-03-04, release date: 2012-01-25, Last modification date: 2024-02-21)

Primary citation

Charton, J.,Gauriot, M.,Guo, Q.,Hennuyer, N.,Marechal, X.,Dumont, J.,Hamdane, M.,Pottiez, V.,Landry, V.,Sperandio, O.,Flipo, M.,Buee, L.,Staels, B.,Leroux, F.,Tang, W.J.,Deprez, B.,Deprez-Poulain, R.
Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-beta hydrolysis.
Eur.J.Med.Chem., 79:184-193, 2014

PubMed Abstract: Insulin degrading enzyme (IDE) is a highly conserved zinc metalloprotease that is involved in the clearance of various physiologically peptides like amyloid-beta and insulin. This enzyme has been involved in the physiopathology of diabetes and Alzheimer's disease. We describe here a series of small molecules discovered by screening. Co-crystallization of the compounds with IDE revealed a binding both at the permanent exosite and at the discontinuous, conformational catalytic site. Preliminary structure-activity relationships are described. Selective inhibition of amyloid-beta degradation over insulin hydrolysis was possible. Neuroblastoma cells treated with the optimized compound display a dose-dependent increase in amyloid-beta levels.

PubMed: 24735644
DOI: 10.1016/j.ejmech.2014.04.009

Experimental method

X-RAY DIFFRACTION (3.2 Å)