Institute of Chemistry, University of Campinas - UNICAMP, P. O. Box, 6154, Campinas, SP, Brazil.
Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands.
Sci Rep. 2017 Jun 14;7(1):3509. doi: 10.1038/s41598-017-03774-x.
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.
天然配体 17β-雌二醇（E2）迄今为止被认为能诱导雌激素受体（ER）的配体结合域（LBD）中独特的激动剂结合的活性构象。在 E2 的存在下，两种亚型 ERα 和 ERβ 都被转录激活，在相似条件下，ERβ 的活性略低于 ERα。这种有趣行为的分子基础主要归因于这些受体的氨基末端结构域的亚型差异。然而，赋予 ER LBD 对 E2 的分子反应差异的结构细节仍然难以捉摸。在这项研究中，我们呈现了一个新的 ERβ LBD 与 E2 结合的晶体结构，其中 H12 呈现出一种类似于拮抗剂 ER 结构的替代构象。结构观察和分子动力学模拟共同提供了证据，表明替代的 ERβ H12 位置可能对应于受体在生理 pH 条件下的稳定构象。我们的发现揭示了 LBD 在 ERβ 亚型较低功能反应中的意外作用。
