Evidence map›Paper›PMID 34476054›Full record

ArticleChemical science2021

Dissecting the activation of insulin degrading enzyme by inositol pyrophosphates and their bisphosphonate analogs.

Sarah Hostachy, Tillmann Utesch, Katy Franke, Gillian Leigh Dornan, David Furkert, Berke Türkaydin, Volker Haucke, Han Sun, Dorothea Fiedler

Open access · diamondAbstract read
In one paragraph

Article in Chemical science, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed
1.0field-weighted citation impact, top 26% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

9 citing papers in PubMed, 14 citations in OpenAlex.

  1. Article
  2. Affinity-Based Interactome Mapping of Inositol Pyrophosphates Reveals 4/6-PP-InsPAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
    Article
  3. Article
  4. Article
  5. Review
  6. Fluorination Influences the Bioisostery of Myo-Inositol Pyrophosphate Analogs.Chemistry (Weinheim an der Bergstrasse, Germany) · 2023
    Article
  7. Article
  8. Article
  9. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 2 institutions in 1 country.

Sarah HostachyLeibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Rössle Str. 10 13125 Berlin Germany fiedler@fmp-berlin.de.ORCID https://orcid.org/0000-0003-1867-9763
Tillmann UteschLeibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Rössle Str. 10 13125 Berlin Germany fiedler@fmp-berlin.de.
Katy FrankeLeibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Rössle Str. 10 13125 Berlin Germany fiedler@fmp-berlin.de.
Gillian Leigh DornanLeibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Rössle Str. 10 13125 Berlin Germany fiedler@fmp-berlin.de.ORCID https://orcid.org/0000-0002-5170-9015
David FurkertLeibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Rössle Str. 10 13125 Berlin Germany fiedler@fmp-berlin.de.ORCID https://orcid.org/0000-0002-6145-5397
Berke TürkaydinLeibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Rössle Str. 10 13125 Berlin Germany fiedler@fmp-berlin.de.ORCID https://orcid.org/0000-0003-1699-0312
Volker HauckeLeibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Rössle Str. 10 13125 Berlin Germany fiedler@fmp-berlin.de.
Han SunLeibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Rössle Str. 10 13125 Berlin Germany fiedler@fmp-berlin.de.
Dorothea FiedlerLeibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Rössle Str. 10 13125 Berlin Germany fiedler@fmp-berlin.de.ORCID https://orcid.org/0000-0002-0798-946X
Leibniz-Forschungsinstitut für Molekulare Pharmakologie · DEHumboldt-Universität zu Berlin · DE

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Inositol poly- and pyrophosphates (InsPs and PP-InsPs) are densely phosphorylated eukaryotic messengers, which are involved in numerous cellular processes. To elucidate their signaling functions at the molecular level, non-hydrolyzable bisphosphonate analogs of inositol pyrophosphates, PCP-InsPs, have been instrumental. Here, an efficient synthetic strategy to obtain these analogs in unprecedented quantities is described - relying on the use of combined phosphate ester-phosphoramidite reagents. The PCP-analogs, alongside their natural counterparts, were applied to investigate their regulatory effect on insulin-degrading enzyme (IDE), using a range of biochemical, biophysical and computational methods. A unique interplay between IDE, its substrates and the PP-InsPs was uncovered, in which the PP-InsPs differentially modulated the activity of the enzyme towards short peptide substrates. Aided by molecular docking and molecular dynamics simulations, a flexible binding mode for the InsPs/PP-InsPs was identified at the anion binding site of IDE. Targeting IDE for therapeutic purposes should thus take regulation by endogenous PP-InsP metabolites into account.

Identifiers

PMID34476054
PMCPMC8372538
OpenAlexW3177777431

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
Read underepoch 390

Registered trials

None linked

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.