# Reproductive Hormones - Biological and Molecular Actions

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $622,138

## Abstract

Project Summary
The estrogen receptor-α (ER) and androgen receptor (AR) are the primary sex steroid hormone receptors in
females and males, respectively. They drive reproduction-related gene expression programs by recruiting a
series of coactivators (CoA) that form large, dynamic protein complexes at gene promoters and enhancers. While
we know a great deal about these sex steroid hormone receptors at a functional and structural level, much less
is known about the CoAs that interact with them at gene promoters and enhancers. Using advanced cryo-electron
microscopy (cryo-EM) approaches, we were able to provide the first 3D understanding of ER engaged with CoA
complexes at a gene enhancer. In this proposal, we plan to expand upon these findings by resolving the structure
of receptor-CoA complexes on chromatin and with a more complete repertoire of proteins that comprise
transcriptional supercomplexes. Also, in preliminary studies, we have made new breakthrough progress toward
resolving an androgen receptor (AR)/SRC-2/DNA holocomplex. Importantly, this will generate a better
understanding of NR/CoA holocomplexes to reveal new insights into the distinct roles for the N-terminal and C-
terminal activation functions (AF-1 and AF-2) of both ER and AR. We will functionally interrogate the structures
identified in our cryo-EM studies using innovative cell-free in vitro assay systems to understand how ER, AR,
SRCs and co-CoAs distinctly regulate chromatin post-translational modifications, chromatin conformation and
gene expression. Steroid receptor coactivators (SRCs) are the central scaffolding components of multi-protein
NR/CoA/co-CoA complexes. New mechanistic insights into NR/CoA function must take into consideration the
3D structural conformation of the modular domains of NRs (DNA binding, AF-1 and AF-2 domains), CoAs and
chromatin topology to generate conceptually novel insights into CoA biology and gene regulation by NRs. The
studies proposed here should form a roadmap to therapy that can be used to develop new therapeutic drugs for
reproductive disease states.

## Key facts

- **NIH application ID:** 10370324
- **Project number:** 5R01HD008188-50
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** BERT W O'MALLEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $622,138
- **Award type:** 5
- **Project period:** 1974-09-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370324

## Citation

> US National Institutes of Health, RePORTER application 10370324, Reproductive Hormones - Biological and Molecular Actions (5R01HD008188-50). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10370324. Licensed CC0.

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