ArticleProceedings of the National Academy of Sciences of the United States of America2018
Conservation of coactivator engagement mechanism enables small-molecule allosteric modulators.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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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.
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Who cites it
18 citing papers in PubMed, 33 citations in OpenAlex.
- No Time to Fold: Intrinsically Disordered Microproteins in Action.Biochemistry · 2026Review
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- A dual interaction between RSV NS1 and MED25 ACID domain reshapes antiviral responses.PLoS pathogens · 2025Article
- Short activation domains control chromatin association of transcription factors.bioRxiv : the preprint server for biology · 2025Article
- Proteomimetic Strategy for the Modulation of Intrinsically Disordered Protein MYC.Journal of the American Chemical Society · 2025Article
- Structural basis of human Mediator recruitment by the phosphorylated transcription factor Elk-1.Nature communications · 2025Article
- A Lipopeptidomimetic of Transcriptional Activation Domains Selectively Disrupts the Coactivator Med25 Protein-Protein Interactions.Angewandte Chemie (International ed. in English) · 2024Article
- Molecular switching in transcription through splicing and proline-isomerization regulates stress responses in plants.Nature communications · 2024Article
- Elongin functions as a loading factor for Mediator at ATF6α-regulated ER stress response genes.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Advances in targeting 'undruggable' transcription factors with small molecules.Nature reviews. Drug discovery · 2021Review
- Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain.Journal of medicinal chemistry · 2021Article
- Norstictic Acid Is a Selective Allosteric Transcriptional Regulator.Journal of the American Chemical Society · 2021Article
- Mediator subunit Med15 dictates the conserved "fuzzy" binding mechanism of yeast transcription activators Gal4 and Gcn4.Nature communications · 2021Article
- Drugging Fuzzy Complexes in Transcription.Frontiers in molecular biosciences · 2021Article
- Unexpected specificity within dynamic transcriptional protein-protein complexes.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Selective Modulation of Dynamic Protein Complexes.Cell chemical biology · 2020Review
- Multivalent and Bidirectional Binding of Transcriptional Transactivation Domains to the MED25 Coactivator.Biomolecules · 2020Article
- Twenty years of Mediator complex structural studies.Biochemical Society transactions · 2019Review
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
Abstract
Transcriptional coactivators are a molecular recognition marvel because a single domain within these proteins, the activator binding domain or ABD, interacts with multiple compositionally diverse transcriptional activators. Also remarkable is the structural diversity among ABDs, which range from conformationally dynamic helical motifs to those with a stable core such as a β-barrel. A significant objective is to define conserved properties of ABDs that allow them to interact with disparate activator sequences. The ABD of the coactivator Med25 (activator interaction domain or AcID) is unique in that it contains secondary structural elements that are on both ends of the spectrum: helices and loops that display significant conformational mobility and a seven-stranded β-barrel core that is structurally rigid. Using biophysical approaches, we build a mechanistic model of how AcID forms binary and ternary complexes with three distinct activators; despite its static core, Med25 forms short-lived, conformationally mobile, and structurally distinct complexes with each of the cognate partners. Further, ternary complex formation is facilitated by allosteric communication between binding surfaces on opposing faces of the β-barrel. The model emerging suggests that the conformational shifts and cooperative binding is mediated by a flexible substructure comprised of two dynamic helices and flanking loops, indicating a conserved mechanistic model of activator engagement across ABDs. Targeting a region of this substructure with a small-molecule covalent cochaperone modulates ternary complex formation. Our data support a general strategy for the identification of allosteric small-molecule modulators of ABDs, which are key targets for mechanistic studies as well as therapeutic applications.
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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.