Ligand-Induced Allosteric Effects Governing SR Signaling

Jennifer K. Colucci,Eric A. Ortlund,C. Denise Okafor

doi:10.32527/2019/101382

Abstract

Steroid receptors (SRs) are a class of ligand-regulated transcription factors that regulate gene expression in response to the binding of steroid hormones. Ligand binding drives conformational changes within the SR ligand binding domain that alters the receptors' affinity for coregulator proteins that in turn modulate chromatin state and either promote or block the recruitment of transcriptional machinery to a gene. Structural characterizations of SRs have provided insight into how these conformational rearrangements modulate receptor function, including signaling between the ligand binding pocket and the site of coregulator binding. Here, we review some of the proposed structural mechanisms put forward to explain the ability of ligands to modulate SR function. We also provide a discussion on computational methods that have contributed to the elucidation of SR allosteric regulation. Finally, we consider broader discussions of allostery within the SR family, such as receptor-induced reverse allostery and allosteric binding sites located outside of the canonical ligand interaction site.

Highlights

The steroid hormone receptor (SR) subfamily within nuclear receptors (NR) controls a diverse array of biological processes, including growth, development, immune responses, and various disease states [1]
Using specific SRs as case studies, we summarize findings on a) Allosteric coupling between ligand binding pocket (LBP) and activation function 2 surface (AF-2), via i) a proposed allosteric network in glucocorticoid receptor (GR) and ii) subtype-specific signaling in estrogen receptor (ER) subtypes, b) Mechanisms of antagonism in androgen receptor (AR), and c) selective steroid receptor modulation in progesterone receptor (PR)
Our particular focus has been on local, ligand binding domain (LBD)-specific effects that result from ligand binding, communicating coregulator preferences via induced structural and dynamics changes

Summary

Introduction

The steroid hormone receptor (SR) subfamily within nuclear receptors (NR) controls a diverse array of biological processes, including growth, development, immune responses, and various disease states [1]. Upon binding to endogenous cholesterol-derived steroid hormones, SRs translocate from the cytoplasm to the nucleus to interact with specific DNA sequences and regulate downstream gene transcription The ability of these receptors to control diverse, tissue-specific processes in response to ligand binding has established them as high-value pharmaceutical targets [2]. Ligand binding to the ligand binding pocket (within the LBD) initiates the allosteric transmission of information that drives a cascade of processes to regulate gene transcription This cascade includes the release of bound chaperone proteins [3], nuclear translocation [4], homo- or hetero-dimerization [5], association with response elements within DNA promoters [6], and binding of coregulatory proteins [7]. Our primary focus in this review rests on describing the local effects in SRs that accompany and/or permit ligand-regulated allostery, including structural reorganizations that facilitate shorter-range coupling between LBP and AF-2 or nonorthosteric binding surfaces on the LBD. We provide brief discussions on i) receptor-induced reverse allostery and ii) allosteric sites that might be relevant across the SR subfamily

Interdomain Allostery in NRs

Computational Methods to Facilitate Investigation of NR Allostery

Structural Mechanisms of LBP-AF-2 Coupling

LBP-AF-2 coupling

Computationally-Proposed Allosteric Binding Pockets Distinct from the LBP

Receptor-Induced Reverse Allostery

Allosteric Sites Common to all SRs

Summary and Future Perspectives