Distinct Mineralocorticoid Receptor Activation Drives Different Side Effects of Glucocorticoid Drugs Restricted; Files Only

Abstract

Glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) are steroid hormone receptors that play important roles in metabolism. Their evolutionary intimacy results in their similar ligand binding domain (LBD) structure, allowing glucocorticoid (GC) to bind to both receptors. Upon activation by GC binding, the receptors translocate into the nucleus and regulate transcription. GR suppresses pro-inflammatory transcription, while MR regulates electrolyte transportation. Abnormal activation of MR underlies disorders like hypertension and fibrosis, which is a concern of GC drugs that simultaneously activate MR when targeting GR for immunosuppressive efficacies. Prednisolone and methylprednisolone are synthetic GC drugs. Past studies have confirmed that methylprednisolone has a better immunosuppressive efficacy than prednisolone, which is also supported by previous research of our lab on their interactions with GRLBD. However, the molecular mechanisms of interaction between the GC drugs and MR remain unknown. In this study, we proved that methylprednisolone induces less MR-mediated transactivation than prednisolone. Biochemical and biophysical investigations of ligand-bound MR LBD showed that compared to MR LBD-prednisolone, MR LBD-methylprednisolone complex is less stable with a higher affinity to corepressors. Structural analysis will be performed by X-ray crystallography to unveil the interactions between MR LBD and GC drugs focusing on the C6 methyl group, which is the only structural difference between prednisolone and methylprednisolone. 

Table of Contents

I. Introduction

II. Materials and Methods

III. Results

Figures for Results

IV. Discussion and Future Directions

References

 

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Molecular
Keyword	mineralocorticoid receptor methylprednisolone prednisolone glucocorticoids
Committee Chair / Thesis Advisor	Liu, Xu, Emory University
Committee Members	Rieder, Leila, Emory University Cole, Megan, Emory University

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