Molecular Graphics and Computation Facility, College of Chemistry , University of California , Berkeley 94720 , California United States.
Department of Environmental Toxicology , University of California , Davis 95616 , California United States.
J Phys Chem B. 2019 Sep 12;123(36):7657-7666. doi: 10.1021/acs.jpcb.9b05654. Epub 2019 Sep 3.
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.
雄激素受体 (AR) 是一种甾体激素核受体，它与内源性雄激素配体（激动剂），如睾酮和二氢睾酮（DHT）结合后，改变基因转录，产生多种生物学效应。抗雄激素药物，如比卡鲁胺和羟基氟他胺，在没有雄激素的情况下作为激动剂起作用，而在存在雄激素或高浓度时则作为拮抗剂起作用。AR 的激动剂和拮抗剂的原子水平作用机制尚未得到很好的描述。因此，在这项研究中，进行了多次 1 μs 分子动力学 (MD)、对接模拟和扰动响应分析，以更全面地探索激动剂或拮抗剂与 AR 之间的相互作用的性质，以及与不同配体相互作用时 AR 诱导的构象变化。我们描述了配体进入/退出的机制，并发现螺旋-12 和附近的结构基序在这个过程中动态响应。建模表明，激动剂和拮抗剂/激动剂与 Thr877/Asn705 形成氢键，而拮抗剂则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激活剂结合位点处残基的迁移率，而拮抗剂的结合降低了这些重要位点的迁移率。还确定了一个新的位点作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 结构和动力学的影响。
