Evidence map›Paper›PMID 42049022›Full record

ArticleStructure (London, England : 1993)2026

Mechanistic design of cell-penetrating disruptors for phospho-dependent TACC3-CHC interaction.

Vanda Gunning, Matthew Batchelor, Krista K Alexander, Martin Walko, Taylor C Dill, Selena G Burgess, Stephen J Royle, Eileen J Kennedy, Richard Bayliss

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Structure (London, England : 1993), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
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

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

9 authors.

Vanda GunningAstbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK.
Matthew BatchelorAstbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK.
Krista K AlexanderDivision of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Martin WalkoAstbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK; School of Chemistry, Faculty of Engineering and Physical Sciences, University of Leeds, Leeds, UK.
Taylor C DillDivision of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Selena G BurgessAstbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK.
Stephen J RoyleCentre for Mechanochemical Cell Biology, Warwick Medical School, University of Warwick, Coventry, UK. Electronic address: s.j.royle@warwick.ac.uk.
Eileen J KennedyDivision of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: eileen.kennedy@unc.edu.
Richard BaylissAstbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK. Electronic address: r.w.bayliss@leeds.ac.uk.

Funding

Targeting WASF3 to suppress metastasisR01GM134168 · NIGMS · UNIVERSITY OF GEORGIA · PI KENNEDY, EILEEN J · 2019 to 2022
$1.2M
NIGMS NIH HHS R01 GM134168Wellcome Trust
6 · The paper itself

Abstract

Mitotic spindle stability is enhanced through microtubule crosslinking by a complex formed when an α helix in transforming acidic coiled-coil 3 (TACC3) binds to the helical repeats of the heavy chain of clathrin (CHC). Here, we show that the phosphorylation of TACC3 at S558 modulates the interaction by overcoming the electrostatic repulsion between K507 of CHC and basic residues in TACC3. Leveraging this insight, we optimized the sequence using peptide arrays to develop a hydrocarbon-stapled peptide (SP TACC3) that binds CHC with over 400-fold higher affinity than the native sequence, disrupting the interaction. The crystal structure of the SP TACC3-CHC complex reveals the contribution of additional polar and hydrophobic contacts to the enhanced interaction. SP TACC3 penetrates cells and displaces TACC3 from the mitotic spindle, causing a delay in mitotic progression in two out of three cancer cell lines. This work showcases a strategy for targeting the TACC3-CHC interaction with hydrocarbon-stapled peptides in a cellular context for potential cancer therapies.

Indexed as

Cell-Penetrating PeptidesClathrinMicrotubule-Associated ProteinsBinding SitesCrystallography, X-RayHumansHydrophobic and Hydrophilic InteractionsModels, MolecularPhosphorylationProtein BindingSpindle ApparatusCell-Penetrating PeptidesClathrinMicrotubule-Associated ProteinsTACC3 protein, humanclathrin heavy chaincrystal structurehydrocarbon-stapled peptidemitosisprotein phosphorylationprotein-protein interaction inhibitorsTACC3

Identifiers

PMID42049022
PMCPMC13176776

What OpenQuestion holds

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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.