ArticlePloS one2011
Identification of the allosteric regulatory site of insulysin.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
23 citing papers in PubMed, 40 citations in OpenAlex.
- It Takes Two to Tango: Current Understanding of the Role of M16 Family of Proteases and Their Structural Properties.Biomolecules · 2025Review
- On electrostatic interactions of adenosine triphosphate-insulin-degrading enzyme revealed by quantum mechanics/molecular mechanics and molecular dynamics.Quantitative biology (Beijing, China) · 2024Article
- The evolution of small molecule enzyme activators.RSC medicinal chemistry · 2023Review
- The Insulin-Degrading Enzyme from Structure to Allosteric Modulation: New Perspectives for Drug Design.Biomolecules · 2023Review
- Insulin-Degrading Enzyme Interacts with Mitochondrial Ribosomes and Respiratory Chain Proteins.Biomolecules · 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
- Modulation of Insulin Sensitivity by Insulin-Degrading Enzyme.Biomedicines · 2021Review
- Enzyme kinetics from circular dichroism of insulin reveals mechanistic insights into the regulation of insulin-degrading enzyme.Bioscience reports · 2018Article
- Article
- Catalytic Mechanism of Amyloid-β Peptide Degradation by Insulin Degrading Enzyme: Insights from Quantum Mechanics and Molecular Mechanics Style Møller-Plesset Second Order Perturbation Theory Calculation.Journal of chemical information and modeling · 2018Article
- Article
- Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Targeting Insulin-Degrading Enzyme to Treat Type 2 Diabetes Mellitus.Trends in endocrinology and metabolism: TEM · 2016Review
- 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
- Structure-activity relationships of imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme.European journal of medicinal chemistry · 2015Article
- Article
- Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-β hydrolysis.European journal of medicinal chemistry · 2014Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundInsulin degrading enzyme (IDE) is responsible for the metabolism of insulin and plays a role in clearance of the Aβ peptide associated with Alzheimer's disease. Unlike most proteolytic enzymes, IDE, which consists of four structurally related domains and exists primarily as a dimer, exhibits allosteric kinetics, being activated by both small substrate peptides and polyphosphates such as ATP. PRINCIPAL
findingsThe crystal structure of a catalytically compromised mutant of IDE has electron density for peptide ligands bound at the active site in domain 1 and a distal site in domain 2. Mutating residues in the distal site eliminates allosteric kinetics and activation by a small peptide, as well as greatly reducing activation by ATP, demonstrating that this site plays a key role in allostery. Comparison of the peptide bound IDE structure (using a low activity E111F IDE mutant) with unliganded wild type IDE shows a change in the interface between two halves of the clamshell-like molecule, which may enhance enzyme activity by altering the equilibrium between closed and open conformations. In addition, changes in the dimer interface suggest a basis for communication between subunits. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that a region remote from the active site mediates allosteric activation of insulysin by peptides. Activation may involve a small conformational change that weakens the interface between two halves of the enzyme.
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Registered trials
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.