| Title |
Conservation of coactivator engagement mechanism enables small-molecule allosteric modulators
|
|---|---|
| Published in |
Proceedings of the National Academy of Sciences of the United States of America, August 2018
|
| DOI | 10.1073/pnas.1806202115 |
| Pubmed ID | |
| Authors |
Andrew R. Henderson, Madeleine J. Henley, Nicholas J. Foster, Amanda L. Peiffer, Matthew S. Beyersdorf, Kevon D. Stanford, Steven M. Sturlis, Brian M. Linhares, Zachary B. Hill, James A. Wells, Tomasz Cierpicki, Charles L. Brooks, Carol A. Fierke, Anna K. Mapp |
| 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. |
X Demographics
The data shown below were collected from the profiles of 31 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 20 | 65% |
| Czechia | 1 | 3% |
| Canada | 1 | 3% |
| Unknown | 9 | 29% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 16 | 52% |
| Scientists | 14 | 45% |
| Science communicators (journalists, bloggers, editors) | 1 | 3% |
Mendeley readers
The data shown below were compiled from readership statistics for 31 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 31 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 10 | 32% |
| Researcher | 4 | 13% |
| Student > Master | 3 | 10% |
| Student > Bachelor | 2 | 6% |
| Professor | 1 | 3% |
| Other | 3 | 10% |
| Unknown | 8 | 26% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 12 | 39% |
| Chemistry | 7 | 23% |
| Agricultural and Biological Sciences | 2 | 6% |
| Social Sciences | 1 | 3% |
| Psychology | 1 | 3% |
| Other | 0 | 0% |
| Unknown | 8 | 26% |
Attention Score in Context
This research output has an Altmetric Attention Score of 18. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 21 January 2019.
All research outputs
#1,950,355
of 24,622,191 outputs
Outputs from Proceedings of the National Academy of Sciences of the United States of America
#24,196
of 101,438 outputs
Outputs of similar age
#40,025
of 338,069 outputs
Outputs of similar age from Proceedings of the National Academy of Sciences of the United States of America
#411
of 915 outputs
Altmetric has tracked 24,622,191 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 92nd percentile: it's in the top 10% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 101,438 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 38.8. This one has done well, scoring higher than 76% of its peers.
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