Abstract
The natural ligand 17β-estradiol (E2) is so far believed to induce a unique agonist-bound active conformation in the ligand binding domain (LBD) of the estrogen receptors (ERs). Both subtypes, ERα and ERβ, are transcriptionally activated in the presence of E2 with ERβ being somewhat less active than ERα under similar conditions. The molecular bases for this intriguing behavior are mainly attributed to subtype differences in the amino-terminal domain of these receptors. However, structural details that confer differences in the molecular response of ER LBDs to E2 still remain elusive. In this study, we present a new crystallographic structure of the ERβ LBD bound to E2 in which H12 assumes an alternative conformation that resembles antagonist ERs structures. Structural observations and molecular dynamics simulations jointly provide evidence that alternative ERβ H12 position could correspond to a stable conformation of the receptor under physiological pH conditions. Our findings shed light on the unexpected role of LBD in the lower functional response of ERβ subtype.
Highlights
Estrogen receptors (ERs) are transcription factors involved in several biological processes, such as the growth, development and cell differentiation, including important regulatory functions within the reproductive and central nervous systems, mammary glands, and bone tissues, among others
We present a new crystal structure of human ERβ ligand binding domain (LBD) bound to E2, where the C-terminal helix 12 (H12) is packed towards the receptor in an alternative conformation that closely resembles that of estrogen receptors (ERs) LBDs bound to antagonist ligands
An alternative structure of ERβ LBD bound to E2 reveals H12 in an antagonist-like conformation
Summary
Estrogen receptors (ERs) are transcription factors involved in several biological processes, such as the growth, development and cell differentiation, including important regulatory functions within the reproductive and central nervous systems, mammary glands, and bone tissues, among others. Our structural analysis and molecular dynamics (MD) simulations of ER subtypes and mutants provide evidence that H12 of the ERβ LBD is not as stable as ERα LBD H12 in its active canonical conformation. Extensive (3.5 microseconds) MD simulations were carried out to map the free-energy landscape across the conformational space spanning both the canonical and the newly determined ERβ LBD-E2 liganded structures.
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