The marionette mechanism of domain-domain communication in the antagonist, agonist, and coactivator responses of the estrogen receptor.
The marionette mechanism of domain-domain communication in the antagonist, agonist, and coactivator responses of the estrogen receptor.
复制标题
DOI：
10.1073/pnas.2216906120
复制
发表时间：
2023-02-07
影响因子：
11.1
通讯作者：
Wolynes, Peter G.
中科院分区：
文献类型：
--
作者：
Chen, Xun;Jin, Shikai;Chen, Mingchen;Bueno, Carlos;Wolynes, Peter G.
雌激素受体的状态被用作乳腺癌临床管理适当方法的指标。了解全长雌激素受体的结构及其与不同配体和肽结合时的构象变化机制有助于设计治疗方案。在这项工作中，我们使用粗粒度模拟，采用AWSEM-3SPN. 2C力场来预测人类雌激素受体α（hERα）与配体和DNA结合时的结构和动力学。受体的柔性区域经历集体运动，很像木偶的舞蹈，放大结构域-配体构象运动，以便在拮抗剂或激动剂结合时以不同的方式将配体结合传递到DNA结合结构域。人雌激素受体α（human estrogen receptor α，hERα）参与生长、发育和组织稳态的调节。与受体的配体结合结构域（LBD）结合的激动剂导致辅激活因子的募集和基因表达的增强。相反，拮抗剂与LBD结合并阻断辅活化剂的结合，从而降低基因表达。在这项工作中，我们进行了模拟，使用AWSEM（缔合记忆，水介导，结构和能量模型）-套件力场沿着的3SPN. 2C力场的DNA预测hERα的结构和研究其结合DNA和辅激活剂时的动力学。通过模拟拮抗剂结合的hERα和激动剂结合的hERα本身以及沿着结合的DNA和辅激活剂，主成分分析和自由能景观分析捕获激动剂结合的hERα的结构域-结构域通信途径。这种通讯是通过铰链结构域介导的，铰链结构域通常是内在无序的。当拮抗剂或激动剂与配体结合域结合时，这些无序的片段以不同的方式扭曲，就像操纵木偶的绳子一样操纵铰链域。
The status of estrogen receptors is used as an indicator of the proper approach to the clinical management of breast cancer. Knowledge of the structure of full-length estrogen receptors and their mechanisms of conformational change when binding with different ligands and peptides can help to design therapies. In this work, we use coarse-grained simulations that employ the AWSEM-3SPN.2C forcefield to predict the structure and dynamics of the human estrogen receptor α (hERα) when bound to ligands and to DNA. The flexible regions of the receptors undergo a collective motion, much like the dancing of a marionette that amplifies domain–ligand conformational motions so as to communicate ligand binding to the DNA-binding domain in different ways when antagonists or agonists bind. The human estrogen receptor α (hERα) 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 hERα and study its dynamics when binding to DNA and coactivators. Using simulations of antagonist-bound hERα and agonist-bound hERα 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 hERα. 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.
登录
查看更多内容
影响因子：
3.3
作者：
Chen, Mingchen;Chen, Xun;Wolynes, Peter G.
通讯作者：
Wolynes, Peter G.
DOI：
10.1073/pnas.0709915104
发表时间：
2007-12-11
影响因子：
11.1
作者：
Ferreiro, Diego U.;Hegler, Joseph A.;Wolynes, Peter G.
通讯作者：
Wolynes, Peter G.
DOI：
10.1101/sqb.1986.051.01.088
发表时间：
1986-01-01
期刊：
COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY
影响因子：
--
作者：
GREEN, S;KUMAR, V;CHAMBON, P
通讯作者：
CHAMBON, P
与获能有关的因素和途径：它们是如何调节的？
影响因子：
--
作者：
Jin SK;Yang WX
通讯作者：
Yang WX
具有一个原子层通道的 FinFET
影响因子：
16.6
作者：
Chen, Mao-Lin;Sun, Xingdan;Han, Zheng
通讯作者：
Han, Zheng