3D model of amphioxus steroid receptor complexed with estradiol

Michael Baker,David Chang

doi:10.1038/npre.2009.3316.1

Abstract

AbstractThe origins of signaling by vertebrate steroids are not fully understood. An important advance was the report that an estrogen-binding steroid receptor [SR] is present in amphioxus, a basal chordate with a similar body plan as vertebrates. To investigate the evolution of estrogen binding to steroid receptors, we constructed a 3D model of amphioxus SR complexed with estradiol. This 3D model indicates that although the SR is activated by estradiol, some interactions between estradiol and human ER[alpha] are not conserved in the SR, which can explain the low affinity of estradiol for the SR. These differences between the SR and ER[alpha] in the steroid-binding domain are sufficient to suggest that another steroid is the physiological regulator of the SR. The 3D model predicts that mutation of Glu-346 to Gln will increase the affinity of testosterone for amphioxus SR and elucidate the evolution of steroid binding to nuclear receptors.

Highlights

Estradiol has diverse physiological actions in vertebrates [1,2,3], many of which are mediated by binding to the estrogen receptor [ER], a member of the nuclear receptor family, which is a large and diverse family of transcription factors [4,5,6,7,8]
Phylogenetic analysis of vertebrate steroid receptors shows that the ER is separate from the androgen receptor (AR), progesterone receptor (PR), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) [4, 6, 7, 9], which correlates with their steroid specificity
Our 3D model of amphioxus SR predicts that mutation of Glu-346 to Gln will increase the affinity of testosterone for amphioxus SR and elucidate the evolution of steroid binding to nuclear receptors

Summary

Introduction

Estradiol has diverse physiological actions in vertebrates [1,2,3], many of which are mediated by binding to the estrogen receptor [ER], a member of the nuclear receptor family, which is a large and diverse family of transcription factors [4,5,6,7,8]. Some key interactions between estradiol and human ERα are conserved in amphioxus SR, which can explain the activation of SR by E2 and the lack of response to 3-ketosteroids.

Results

Conclusion