# Mechanism of Hsp90-Dependent Glucocorticoid Receptor Activation

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $24,565

## Abstract

PROJECT SUMMARY/ABSTRACT
 Maintaining protein homeostasis is fundamental for organismal survival. Integral to this process are
molecular chaperones, including the highly abundant and evolutionary conserved heat shock protein 90 (Hsp90),
which facilitates the folding of hundreds of `client' proteins. Hsp90 clients are enriched in signaling molecules,
such as kinases and transcription factors, which regulate cell growth and survival. Consequently, many Hsp90
clients are oncoproteins, making Hsp90 an important pharmaceutical target for cancer with Hsp90 inhibitors
currently in clinical oncology trials. However, a mechanistic understanding of how Hsp90 remodels client proteins
is lacking and precludes further advancements in Hsp90-targeted cancer therapies. One class of clinically
important Hsp90 clients are the steroid hormone receptors (SHRs), steroid-activated transcription factors that
control cell growth and development and are potent therapeutic targets for cancer. One SHR, the glucocorticoid
receptor (GR), is a model Hsp90 client that goes through a `chaperone cycle', where GR binds to Hsp90, Hsp70,
and a variety of co-chaperones to maintain its activity. Multiple aspects of GR function are regulated by Hsp90,
including ligand binding, nuclear translocation, and chromatin binding—all essential steps in GR-dependent gene
expression regulation. Understanding the mechanism by which Hsp90 regulates GR will elucidate how Hsp90
influences a myriad of clinically important signaling pathways, advancing efforts to target this master regulator
for cancer therapies. To investigate how Hsp90 refolds and reactivates GR, I determined the cryo-EM structure
of the native, active GR ligand binding domain (LBD) bound to Hsp90, revealing, for the first time, the mechanism
of Hsp90-mediated conformational remodeling of a client. I will build on the knowledge from my structure to
determine how Hsp90 regulates GR functions downstream of ligand binding. Aim 1 will determine how Hsp90
regulates GR nuclear translocation with the aid of the Hsp90 co-chaperones FK506 binding protein 51 (FKBP51)
and FKBP52, which regulate GR nuclear translocation by connecting to dynein. Using cryo-EM as well as in vitro
and in vivo biochemical assays, I will determine how the FKBPs incorporate with the GR-chaperone cycle,
influence GR conformation, and connect GR:Hsp90 to dynein for nuclear translocation. Aim 2 will investigate
how Hsp90 regulates GR binding to DNA and chromatin. Previous studies have suggested Hsp90 is inhibitory
to GR DNA and chromatin binding, but the mechanism of inhibition is unknown. Using the first recombinantly
purified multidomain GR, containing both the LBD and DNA binding domain (DBD), I will determine how the GR
chaperone cycle modulates GR binding to DNA and chromatin substrates using cryo-EM and in vitro biochemical
binding assays. This project encompasses structural biology, biochemistry, and cell-based assays, while bridging
the protein folding and chrom...

## Key facts

- **NIH application ID:** 10454138
- **Project number:** 5F31CA265084-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Chari Noddings
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $24,565
- **Award type:** 5
- **Project period:** 2021-08-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454138

## Citation

> US National Institutes of Health, RePORTER application 10454138, Mechanism of Hsp90-Dependent Glucocorticoid Receptor Activation (5F31CA265084-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10454138. Licensed CC0.

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