Center for Theoretical Biological Physics, Rice University, Houston, TX 77005.
Department of Chemistry, Rice University, Houston, TX 77005.
Proc Natl Acad Sci U S A. 2023 Feb 7;120(6):e2216906120. doi: 10.1073/pnas.2216906120. Epub 2023 Feb 2.
The human estrogen receptor (hER) is involved in the regulation of growth, development, and tissue homeostasis. Agonists that bind to the receptor's ligand-binding domain (LBD) lead to recruitment of coactivators and the enhancement of gene expression. In contrast, antagonists bind to the LBD and block the binding of coactivators thus decreasing gene expressions. In this work, we carry out simulations using the AWSEM (Associative memory, Water mediated, Structure and Energy Model)-Suite force field along with the 3SPN.2C force field for DNA to predict the structure of hER and study its dynamics when binding to DNA and coactivators. Using simulations of antagonist-bound hER and agonist-bound hER by themselves and also along with bound DNA and coactivators, principal component analyses and free energy landscape analyses capture the pathway of domain-domain communication for agonist-bound hER. This communication is mediated through the hinge domains that are ordinarily intrinsically disordered. These disordered segments manipulate the hinge domains much like the strings of a marionette as they twist in different ways when antagonists or agonists are bound to the ligand-binding domain.
人类雌激素受体（hER）参与调节生长、发育和组织稳态。与受体的配体结合域（LBD）结合的激动剂导致共激活因子的募集，并增强基因表达。相比之下，拮抗剂与 LBD 结合并阻止共激活因子的结合，从而减少基因表达。在这项工作中，我们使用 AWSEM（联想记忆、水介导、结构和能量模型）套件力场和 3SPN.2C 力场进行模拟，以预测 hER 的结构，并研究其与 DNA 和共激活因子结合时的动力学。通过模拟单独结合 DNA 和共激活因子的拮抗剂结合 hER 和激动剂结合 hER，主成分分析和自由能景观分析捕获了激动剂结合 hER 的域-域通讯途径。这种通讯是通过铰链域介导的，铰链域通常是固有无序的。当拮抗剂或激动剂与配体结合域结合时，这些无序片段像操纵木偶的线一样操纵铰链域，它们以不同的方式扭曲。
