ArticleThe Journal of biological chemistry2012
Anion activation site of insulin-degrading enzyme.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 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
18 citing papers in PubMed, 33 citations in OpenAlex.
- Discovery of a pyridine-piperazine-based small molecule that enhances the activity of peptidase neurolysin.The Journal of pharmacology and experimental therapeutics · 2026Article
- 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
- Review
- Inhibition of Insulin Degrading Enzyme to Control Diabetes Mellitus and its Applications on some Other Chronic Disease: a Critical Review.Pharmaceutical research · 2022Review
- Dissecting the activation of insulin degrading enzyme by inositol pyrophosphates and their bisphosphonate analogs.Chemical science · 2021Article
- Enzyme kinetics from circular dichroism of insulin reveals mechanistic insights into the regulation of insulin-degrading enzyme.Bioscience reports · 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
- Article
- Proteasome Activity Is Affected by Fluctuations in Insulin-Degrading Enzyme Distribution.PloS one · 2015Article
- 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
- Conformational states and recognition of amyloidogenic peptides of human insulin-degrading enzyme.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic aβ peptide aggregates.PloS one · 2013Article
- Cysteine 904 is required for maximal insulin degrading enzyme activity and polyanion activation.PloS one · 2012Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Insulin-degrading enzyme (IDE) (insulysin) is a zinc metallopeptidase that metabolizes several bioactive peptides, including insulin and the amyloid β peptide. IDE is an unusual metallopeptidase in that it is allosterically activated by both small peptides and anions, such as ATP. Here, we report that the ATP-binding site is located on a portion of the substrate binding chamber wall arising largely from domain 4 of the four-domain IDE. Two variants having residues in this site mutated, IDEK898A,K899A,S901A and IDER429S, both show greatly decreased activation by the polyphosphate anions ATP and PPPi. IDEK898A,K899A,S901A is also deficient in activation by small peptides, suggesting a possible mechanistic link between the two types of allosteric activation. Sodium chloride at high concentrations can also activate IDE. There are no observable differences in average conformation between the IDE-ATP complex and unliganded IDE, but regions of the active site and C-terminal domain do show increased crystallographic thermal factors in the complex, suggesting an effect on dynamics. Activation by ATP is shown to be independent of the ATP hydrolysis activity reported for the enzyme. We also report that IDEK898A,K899A,S901A has reduced intracellular function relative to unmodified IDE, consistent with a possible role for anion activation of IDE activity in vivo. Together, the data suggest a model in which the binding of anions activates by reducing the electrostatic attraction between the two halves of the enzyme, shifting the partitioning between open and closed conformations of IDE toward the open form.
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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.