激动剂和拮抗剂与雄激素受体结合的结构动力学。,The Journal of Physical Chemistry B

当前位置： X-MOL 学术 › J. Phys. Chem. B › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

激动剂和拮抗剂与雄激素受体结合的结构动力学。
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2019-09-03 , DOI: 10.1021/acs.jpcb.9b05654
Ettayapuram Ramaprasad Azhagiya Singam ₁ , Phum Tachachartvanich ₂ , Michele A La Merrill ₂ , Martyn T Smith ₃ , Kathleen A Durkin ₁

Affiliation

雄激素受体（AR）是一种类固醇激素核受体，结合其内源性雄性配体（激动剂），睾丸激素和二氢睾丸激素（DHT）后，可改变基因转录，从而产生多种生物学效应。抗雄激素，例如比卡鲁胺和羟基氟他胺药物，在没有雄激素的情况下起激动剂的作用，在存在或高浓度下起拮抗剂的作用。AR的激动剂和拮抗剂的原子水平作用机理不太清楚。因此，在这项研究中，进行了多个1μs分子动力学（MD），对接模拟和微扰响应分析，以更充分地探索激动剂或拮抗剂与AR之间相互作用的本质以及与AR相互作用后在AR中诱导的构象变化。不同的配体。我们表征了配体进入/退出的机制，并发现在该过程中helic-12和附近的结构基序动态响应。建模表明，激动剂和拮抗剂/激动剂与Thr877 / Asn705形成氢键，并且拮抗剂之间不存在这种相互作用。激动剂与AR的结合增加了变构位点和共活化剂结合位点上残基的迁移率，而拮抗剂的结合则降低了这些重要位点上的迁移率。一个新的站点也被确定为变构结合的潜在表面。这些结果揭示了激动剂和拮抗剂对AR的结构和动力学的影响。建模表明，激动剂和拮抗剂/激动剂与Thr877 / Asn705形成氢键，并且拮抗剂之间不存在这种相互作用。激动剂与AR的结合增加了变构位点和共活化剂结合位点上残基的迁移率，而拮抗剂的结合则降低了这些重要位点上的迁移率。一个新的站点也被确定为变构结合的潜在表面。这些结果揭示了激动剂和拮抗剂对AR的结构和动力学的影响。建模表明，激动剂和拮抗剂/激动剂与Thr877 / Asn705形成氢键，并且拮抗剂之间不存在这种相互作用。激动剂与AR的结合增加了变构位点和共活化剂结合位点上残基的迁移率，而拮抗剂的结合则降低了这些重要位点上的迁移率。一个新的站点也被确定为变构结合的潜在表面。这些结果揭示了激动剂和拮抗剂对AR的结构和动力学的影响。

"点击查看英文标题和摘要"

Structural Dynamics of Agonist and Antagonist Binding to the Androgen Receptor.

Androgen receptor (AR) is a steroid hormone nuclear receptor which upon binding its endogenous androgenic ligands (agonists), testosterone and dihydrotestosterone (DHT), alters gene transcription, producing a diverse range of biological effects. Antiandrogens, such as the pharmaceuticals bicalutamide and hydroxyflutamide, act as agonists in the absence of androgens and as antagonists in their presence or in high concentration. The atomic level mechanism of action by agonists and antagonists of AR is less well characterized. Therefore, in this study, multiple 1 μs molecular dynamics (MD), docking simulations, and perturbation-response analyses were performed to more fully explore the nature of interaction between agonist or antagonist and AR and the conformational changes induced in the AR upon interaction with different ligands. We characterized the mechanism of the ligand entry/exit and found that helix-12 and nearby structural motifs respond dynamically in that process. Modeling showed that the agonist and antagonist/agonist form a hydrogen bond with Thr877/Asn705 and that this interaction is absent for antagonists. Agonist binding to AR increases the mobility of residues at allosteric sites and coactivator binding sites, while antagonist binding decreases mobility at these important sites. A new site was also identified as a potential surface for allosteric binding. These results shed light on the effect of agonists and antagonists on the structure and dynamics of AR.

更新日期：2019-09-04

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文