Stringing along the estrogen receptor to engage with DNA.
Stringing along the estrogen receptor to engage with DNA.
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DOI：
10.1073/pnas.2300608120
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发表时间：
2023-03-14
影响因子：
11.1
通讯作者：
Katzenellenbogen, John A.
中科院分区：
文献类型：
--
作者：
Katzenellenbogen, John A.
雌激素受体α（ERα）是一种受配体调控的转录因子，属于核受体超家族成员，在人类健康和疾病中起着重要作用。ERα与内源性激素雌二醇一起调节雌性生殖组织的发育和维持，并调节许多其他非生殖器官的正常功能，如骨、脑、血管、肝和胰腺。它也是许多乳腺癌的主要驱动因素，并且是基于阻断其活性的抗雌激素（如他莫昔芬或氟维司群）或阻止雌二醇产生的芳香酶抑制剂（如来曲唑）的内分泌疗法的靶点。可以理解的是，人们对阐明雌激素受体的结构和了解它在显示其活性谱时如何在机械水平上发挥作用有着浓厚的兴趣。莱斯大学的Wolynes研究小组最近利用先进的计算机模拟技术做出了重大贡献，阐明了ERα与DNA相互作用时的动态运动--由激活配体的结合触发--这是其作为转录因子的主要作用的基本第一步。他们提出的有趣机制可能与核受体超家族的大约50个其他成员有关（2）。在过去的半个世纪中，通过生物化学和分子方法以及NMR、X射线晶体学和冷冻电子显微镜（CryoEM）结构测定的不断进步，ERα以及核受体超家族其他成员的许多基本结构特征已得到阐明（2）。ERα的基本结构特征（图1A和图B）包括两个折叠良好的结构域，一个中心DNA结合结构域（DBD，C结构域）和一个配体结合结构域（LBD，E结构域），它们连接并侧翼有三个非结构化序列，N末端的A/B结构域，DBD和LBD之间的接头或铰链D结构域，以及一个短的C末端F结构域。ERα通常作为二聚体发挥功能，主要的二聚体相互作用位点位于LBD中心（图1C）。激活配体与ERα结合后，辅调节因子在DNA结合的ERα二聚体上组装，将其功能性地连接到控制基因转录的蛋白质基础复合物上（3）。除了这个简单的配体结合和DNA
Estrogen receptor alpha (ERα), a ligand-regulated transcription factor and member of the large nuclear receptor superfamily of transcription factors, plays major roles in health and disease. Together with the endogenous hormone, estradiol, ERα regulates the development and maintenance of female reproductive tissues and modulates the normal function of many other nonreproductive organs, such as bone, brain, vasculature, liver and pancreas. It is also the principal driver of many breast cancers and is the target of endocrine therapies based on antiestrogens (such as tamoxifen or fulvestrant) that block its activity, or aromatase inhibitors (such as letrozole) that prevent the production of estradiol. Understandably, there has been a keen and longstanding interest in elucidating the structure of the estrogen receptor and understanding how it functions at a mechanistic level as it displays its spectrum of activities. Using advanced computational simulations, the Wolynes group at Rice University has recently made a major contribution (1) that illuminates the dynamic motions that ERα undergoes when—triggered by the binding of activating ligands—it interacts with DNA, the fundamental first step in its primary role as a transcription factor. The intriguing mechanism that they propose is likely to be relevant to the approximately 50 other members of the nuclear receptor superfamily (2). Many of the basic structural features of ERα, as well as those of other members of the nuclear receptor superfamily, have been elucidated over the past half century through progressive advances in biochemical and molecular methods and NMR, X-ray crystallographic, and cryoelectron microscopic (CryoEM) structure determination (2). The basic structural features of ERα (Fig. 1 A and B) comprise two well-folded domains, a central DNA-binding domain (DBD, the C-domain) and a ligand-binding domain (LBD, the E-domain), which are connected and flanked by three unstructured sequences, the A/B domain at the N terminus, the linker or hinge D domain between the DBD and LBD, and a short C-terminal F domain. ERα generally functions as a dimer with the principal dimer interaction site centered in the LBD (Fig. 1C). After activating ligands bind to ERα, coregulating factors then assemble on the DNA-bound ERα dimer to functionally link it to the basal complex of proteins that control gene transcription (3). Beyond this simple lexicon of ligand binding and then DNA
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DOI：
10.1073/pnas.2216906120
发表时间：
2023-02-07
影响因子：
11.1
作者：
Chen, Xun;Jin, Shikai;Chen, Mingchen;Bueno, Carlos;Wolynes, Peter G.
通讯作者：
Wolynes, Peter G.
影响因子：
16.8
作者：
Lou, Xiaohua;Toresson, Gudrun;Gustafsson, Jan-Ake
通讯作者：
Gustafsson, Jan-Ake
影响因子：
16
作者：
Yi, Ping;Wang, Zhao;O'Malley, Bert W.
通讯作者：
O'Malley, Bert W.
影响因子：
64.8
作者：
Chandra, Vikas;Huang, Pengxiang;Hamuro, Yoshitomo;Raghuram, Srilatha;Wang, Yongjun;Burris, Thomas P.;Rastinejad, Fraydoon
通讯作者：
Rastinejad, Fraydoon
影响因子：
16.6
作者：
Huang W;Peng Y;Kiselar J;Zhao X;Albaqami A;Mendez D;Chen Y;Chakravarthy S;Gupta S;Ralston C;Kao HY;Chance MR;Yang S
通讯作者：
Yang S