# Probing transcriptional activation at the molecular level - Equipment Supplement

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $100,526

## Abstract

Project Summary
The protein‐protein interaction network that form between transcriptional coactivators and
activators is dysregulated in every human disease as either a cause or an effect and as such
represents a potentially powerful intervention point for therapeutic development. Yet there is
little knowledge about this PPI network, particularly how binding events in one domain of a
coactivator impacts the global structure and function of the remainder of the domains. We
demonstrated in earlier work funded by NIGMS that we can take advantage of the
conformational plasticity of coactivators to discover covalent chemical co‐chaperones and small
molecules that capture distinct conformational suites of coactivators in vitro and in the cellular
milieu. Thus we are poised to answer fundamental questions regarding coactivators: how does a
local binding event at an ABD (known to change dynamics and local structure) affect the PPI
network of the coactivator, global structural dynamics, and ultimately function. This will not only
increase the resolution of our understanding of the basic biology of transcription but also provide
a framework by which predictions for the best PPIs for transcription‐targeted therapeutics can be
made. Building on the tools and strategies developed in our GM‐funded work, we will define the
molecular recognition rules for coactivator ABDs. In doing so, we will produce a suite of selective
modulators for functionally distinct coactivators. These data will also provide a rigorous
framework and predictive algorithm for the future discovery of selective small molecules and
peptidomimetic inhibitors. Through structural studies of intact coactivator‐activator complexes,
we will expand the molecular recognition model to include the relationship between local
binding‐induced conformational changes and global architectural and functional alterations
within full‐length activators and coactivators.
We request a replacement for our current automated peptide synthesizer (purchased in 2016) in
order to accomplish the goals of the grant, particularly for Project 2. The model we are requesting
also has the capability of synthesizing up to four peptides/peptidomimetics sequentially, leading
to enormous efficiencies since we can then use the instrument in overnight runs. This will
significantly facilitate the accomplishment of the project and due to the unanticipated nature of
the need and the price of such an instrument, it cannot be accommodated in the budget of
GM136356.

## Key facts

- **NIH application ID:** 10604581
- **Project number:** 3R35GM136356-03S1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** ANNA K. MAPP
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $100,526
- **Award type:** 3
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10604581

## Citation

> US National Institutes of Health, RePORTER application 10604581, Probing transcriptional activation at the molecular level - Equipment Supplement (3R35GM136356-03S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10604581. Licensed CC0.

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