Dynamic changes in binding interaction networks of sex steroids establish their non-classical effects

Mónika Bálint,István Horváth,Norbert Jeszenői,Csaba Hetényi,István M Ábrahám

doi:10.1038/s41598-017-14840-9

Mónika Bálint, István Horváth + Show 3 more

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https://doi.org/10.1038/s41598-017-14840-9

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Journal: Scientific Reports	Publication Date: Nov 1, 2017
Citations: 3	License type: open-access

Affiliation: University of Pecs, University of Szeged

Abstract

Non-classical signaling in the intracellular second messenger system plays a pivotal role in the cytoprotective effect of estradiol. Estrogen receptor is a common target of sex steroids and important in mediating estradiol-induced neuroprotection. Whereas the mechanism of genomic effects of sex steroids is fairly understood, their non-classical effects have not been elucidated completely. We use real time molecular dynamics calculations to uncover the interaction network of estradiol and activator estren. Besides steroid interactions, we also investigate the co-activation of the receptor. We show how steroid binding to the alternative binding site of the non-classical action is facilitated by the presence of a steroid in the classical binding site and the absence of the co-activator peptide. Uncovering such dynamic mechanisms behind steroid action will help the structure-based design of new drugs with non-classical responses and cytoprotective potential.

Highlights

Estrogens are responsible for a wide range of biological actions from the regulation of fertility to cytoprotection[1,2,3]
To study the effect of CA binding on structural dynamics of hERα (Fig. 2a,b and Supplementary Video S1), both the CA bound (CA+) and free (CA−) structures of the steroid-free ligand-binding domain (LBD) were investigated (Fig. 2c) for comparison
1μs-long molecular dynamics (MD) calculations were performed to study the structural evolution of the LBD

Summary

Introduction

Estrogens are responsible for a wide range of biological actions from the regulation of fertility to cytoprotection[1,2,3]. Structural dynamics of biding events establishing non-classical E2 action on ERs has not been fully elucidated The lack of such details of molecular mechanisms of neuroprotective actions of estrogens hinders the exploitation of their therapeutic potential. Genomic actions (Fig. 1 top) ANCELS such as EN22, substance A and substance B23 exhibit weak transcriptional activity, selectively activating the non-classical E2 signaling as validated by functional assays[22,23]. The underlying mechanism has not been understood due to the lack of atomic resolution structures of the complexes of effector ligands and ERs. An interesting study[25] proposed an alternative binding site (ABS) of E2 and EN on hERα, further discussed by Norman and co-workers[26], conveying the non-classical actions, analogously to vitamin D receptor[25]. E2 binding to ABS26 does not directly alter gene expression, but rapidly activates the mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) signaling pathway instead (Fig. 1, top)[8,9]

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Conclusion