# Molecular mechanism of Androgen Receptor mediated transcription

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $336,000

## Abstract

Abstract
Transcription factors are key determinants of gene expression. Lipophilic hormonal ligands and accompanying
co-regulatory molecules trigger the activity of transcription factors, including members of the nuclear hormone
receptor (NR) family. AR and its splice variant AR-V7 are NRs that play key roles in prostate cancer development,
and particularly CRPC. Current therapies targeting AR mainly focus on its ligand-binding domain (LBD), which
is not present in AR-V7. Patients that respond initially to those therapies become resistant to them within a few
years. Both AR and AR-V7 must recruit CoRs to be functionally active. Disruption of the AR–CoR interface
inhibits AR activity in both androgen-dependent cells and CRPC cells. Therefore, knowledge of how AR variants
interact with specific CoRs to form a transcriptionally active complex is critical for the design of therapeutics
targeting AR and AR-V7. Our preliminary studies provided the first structural understanding of active NR–CoR
complex assembly and demonstrated that conformational variability has a profound impact on NR-mediated
transcriptional activation.
In this proposal, we hypothesize that AR and its variants have a common set of CoRs, but that the assembly and
three-dimensional arrangement of those CoRs in AR complexes are unique to each and contribute to the
regulation of transcriptional activities. We propose to leverage the complementary expertise of investigators in
NR biology, cryoEM, and image processing to determine the structural basis of transcriptionally active AR
complexes. We will pursue that goal through two specific aims: 1) Solve a high-resolution DNA–AR structure to
identify domain-domain interactions in detail and then compare it to the structure of DNA–AR-V7; and 2) Improve
the resolution of AR–CoR complexes structures to identify detailed interactions and determine the structural
differences in comparison with AR-V7–CoR complexes. Both aims will utilize cryoEM to visualize functional AR–
CoR complexes. The proposed work is significant because the structures will describe the overall interactions in
the system to determine which components should be targeted for therapeutic modulation. A structural
understanding of how AR forms functional dimers and interacts with CoRs to activates gene expression will
provide critical information about the biology of transcription and enable future studies of looking for small-
molecular inhibitors can affect the AR complex arrangement. The proposed multidisciplinary work is innovative
because it employs advanced imaging techniques to achieve unprecedented insights into the structure and
function of AR–CoR complexes, AR heterodimers, and the drugs that target them.

## Key facts

- **NIH application ID:** 10447691
- **Project number:** 5R01GM143380-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Zhao Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $336,000
- **Award type:** 5
- **Project period:** 2021-07-08 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447691

## Citation

> US National Institutes of Health, RePORTER application 10447691, Molecular mechanism of Androgen Receptor mediated transcription (5R01GM143380-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10447691. Licensed CC0.

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