ArticleBiochemistry2008
Molecular bases for the recognition of short peptide substrates and cysteine-directed modifications of human insulin-degrading enzyme.
Article in Biochemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 82 citations in OpenAlex.
- It Takes Two to Tango: Current Understanding of the Role of M16 Family of Proteases and Their Structural Properties.Biomolecules · 2025Review
- The Structures and Functions of VZV Glycoproteins.Current topics in microbiology and immunology · 2023Article
- Exchange Broadening Underlies the Enhancement of IDE-Dependent Degradation of Insulin by Anionic Membranes.ACS omega · 2022Article
- Review
- Exploring the Structural Rearrangements of the Human Insulin-Degrading Enzyme through Molecular Dynamics Simulations.International journal of molecular sciences · 2022Article
- Article
- Dissecting the activation of insulin degrading enzyme by inositol pyrophosphates and their bisphosphonate analogs.Chemical science · 2021Article
- 7,8-Dihydroxyflavone improves cognitive functions in ICV-STZ rat model of sporadic Alzheimer's disease by reversing oxidative stress, mitochondrial dysfunction, and insulin resistance.Psychopharmacology · 2021Article
- Modulation of Insulin Sensitivity by Insulin-Degrading Enzyme.Biomedicines · 2021Review
- The core sequence of PIF competes for insulin/amyloid β in insulin degrading enzyme: potential treatment for Alzheimer's disease.Oncotarget · 2018Article
- Article
- Lipopolysaccharide Potentiates Insulin-Driven Hypoglycemic Shock.Journal of immunology (Baltimore, Md. : 1950) · 2017Article
- Targeting Insulin-Degrading Enzyme to Treat Type 2 Diabetes Mellitus.Trends in endocrinology and metabolism: TEM · 2016Review
- Selective Targeting of Extracellular Insulin-Degrading Enzyme by Quasi-Irreversible Thiol-Modifying Inhibitors.ACS chemical biology · 2015Article
- Dual Exosite-binding Inhibitors of Insulin-degrading Enzyme Challenge Its Role as the Primary Mediator of Insulin Clearance in Vivo.The Journal of biological chemistry · 2015Article
- Insulin-degrading enzyme prevents α-synuclein fibril formation in a nonproteolytical manner.Scientific reports · 2015Article
- Structures of human CCL18, CCL3, and CCL4 reveal molecular determinants for quaternary structures and sensitivity to insulin-degrading enzyme.Journal of molecular biology · 2015Article
- An angiotensin-(1-7) peptidase in the kidney cortex, proximal tubules, and human HK-2 epithelial cells that is distinct from insulin-degrading enzyme.American journal of physiology. Renal physiology · 2015Article
- Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones.Nature · 2014Article
- Effects of polyprenols from pine needles of Pinus massoniana on ameliorating cognitive impairment in a D-galactose-induced mouse model.Age (Dordrecht, Netherlands) · 2014Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Insulin degrading enzyme (IDE) utilizes a large catalytic chamber to selectively bind and degrade peptide substrates such as insulin and amyloid beta (Abeta). Tight interactions with substrates occur at an exosite located approximately 30 A away from the catalytic center that anchors the N-terminus of substrates to facilitate binding and subsequent cleavages at the catalytic site. However, IDE also degrades peptide substrates that are too short to occupy both the catalytic site and the exosite simultaneously. Here, we use kinins as a model system to address the kinetics and regulation of human IDE with short peptides. IDE specifically degrades bradykinin and kallidin at the Pro/Phe site. A 1.9 A crystal structure of bradykinin-bound IDE reveals the binding of bradykinin to the exosite and not to the catalytic site. In agreement with observed high K(m) values, this suggests low affinity of bradykinin for IDE. This structure also provides the molecular basis on how the binding of short peptides at the exosite could regulate substrate recognition. We also found that human IDE is potently inhibited by physiologically relevant concentrations of S-nitrosylation and oxidation agents. Cysteine-directed modifications play a key role, since an IDE mutant devoid of all 13 cysteines is insensitive to the inhibition by S-nitrosoglutathione, hydrogen peroxide, or N-ethylmaleimide. Specifically, cysteine 819 of human IDE is located inside the catalytic chamber pointing toward an extended hydrophobic pocket and is critical for the inactivation. Thiol-directed modification of this residue likely causes local structural perturbation to reduce substrate binding and catalysis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.