An alternative conformation of ER beta bound to estradiol reveals H12 in a stable antagonist position

Author(s)

Souza, Paulo C. T. ; Textor, Larissa C. ; Melo, Denise C. ; Nascimento, Alessandro S. ; Skaf, Munir S. ; Polikarpov, Igor

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 7, JUN 14 2017.
• Web of Science Citations: 5

Abstract

The natural ligand 17 beta-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, ER alpha and ER beta, are transcriptionally activated in the presence of E2 with ER beta being somewhat less active than ERa 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 ER beta 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 ER beta 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 ER beta subtype. (AU)

• FAPESP's process: 13/08293-7 - CCES - Center for Computational Engineering and Sciences
• Grantee: Munir Salomao Skaf
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 14/22007-0 - Coarse-graining molecular dynamics simulations of TLR4 complexes
• Grantee: Paulo Cesar Telles de Souza
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 12/24750-6 - Relationship between obesity and the TLR4 receptor: New studies by molecular dynamics simulations
• Grantee: Paulo Cesar Telles de Souza
• Support Opportunities: Scholarships in Brazil - Post-Doctoral