Molecular Dynamics Simulations Revealed the Regulation of Ligands to the Interactions between Androgen Receptor and Its Coactivator.
Molecular Dynamics Simulations Revealed the Regulation of Ligands to the Interactions between Androgen Receptor and Its Coactivator.
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分子动力学模拟揭示配体对雄激素受体与其共激活剂相互作用的调节
DOI：
10.1021/acs.jcim.8b00283
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发表时间：
2018-08-27
影响因子：
5.6
通讯作者：
Hou T
中科院分区：
文献类型：
--
作者：
Liu N;Zhou W;Guo Y;Wang J;Fu W;Sun H;Li D;Duan M;Hou T
雄激素受体(AR)在基因表达调控、性表型维持和前列腺癌(PCa)的发生发展中起着重要作用。AR配体结合域(LBD)与其共激活子之间的通讯是AR激活的关键。目前尚不清楚配体结合将如何影响AR-辅活化子相互作用。在这项工作中，我们用分子动力学(MD)模拟研究了配体结合对AR-辅活化子通讯的影响。结果表明，配体结合调节功能位点AF-2上的残基相互作用。研究了配体到共激活剂的变构途径，包括辅助激活剂螺旋3(H3)、螺旋4(H4)、H3和H4之间的环(L3)和螺旋12(H12)以及配体。此外，功能位点BF-3上残基的相互作用，特别是在AF-2和BF-3交界处的相互作用也受到配体的影响。MM/GBSA自由能计算表明，共激活剂与apo-AR之间的结合亲和力大致弱于共激活剂与拮抗剂ARs之间的亲和力，但强于辅激活剂与激动剂ARs之间的亲和力。结果表明，长程静电相互作用和构象熵是影响结合自由能的主要因素。此外，AR-LBD上的F876L突变影响了配体到辅活化子的变构途径，这可能是点突变导致对苯扎鲁胺等拮抗剂耐受的原因。我们的研究将有助于开发新的抗前列腺癌的候选药物。
The androgen receptor (AR) plays important roles in gene expression regulation, sexual phenotype maintenance, and prostate cancer (PCa) development. The communications between the AR ligand-binding domain (LBD) and its coactivator are critical to the activation of AR. It is still unclear how the ligand binding would affect the AR-coactivator interactions. In this work, the effects of the ligand binding on the AR-coactivator communications were explored by molecular dynamics (MD) simulations. The results showed that the ligand binding regulates the residue interactions in the function site AF-2. The ligand-to-coactivator allosteric pathway, which involves the coactivator, helix 3 (H3), helix 4 (H4), the loop between H3 and H4 (L3), and helix 12 (H12), and ligands, was characterized. In addition, the interactions of residues on the function site BF-3, especially on the boundary of AF-2 and BF-3, are also affected by the ligands. The MM/GBSA free energy calculations demonstrated that the binding affinity between the coactivator and apo-AR is roughly weaker than those between the coactivator and antagonistic ARs but stronger than those between the coactivator and agonistic ARs. The results indicated that the long-range electrostatic interactions and the conformational entropies are the main factors affecting the binding free energies. In addition, the F876L mutation on AR-LBD affects the ligand-to-coactivator allosteric pathway, which could be the reason for point mutation induced tolerance for the antagonistic drugs such as enzalutamide. Our study would help to develop novel drug candidates against PCa.
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影响因子：
5.5
作者：
Goetz, Andreas W.;Williamson, Mark J.;Xu, Dong;Poole, Duncan;Le Grand, Scott;Walker, Ross C.
通讯作者：
Walker, Ross C.
影响因子：
7.7
作者：
Balbas MD;Evans MJ;Hosfield DJ;Wongvipat J;Arora VK;Watson PA;Chen Y;Greene GL;Shen Y;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
4.1
作者：
LAMBRAKOS, SG;BORIS, JP;NAGUMO, M
通讯作者：
NAGUMO, M
影响因子：
28.2
作者：
Korpal, Manav;Korn, Joshua M.;Zhu, Ping
通讯作者：
Zhu, Ping
影响因子：
4.8
作者：
He, B;Minges, JT;Wilson, EM
通讯作者：
Wilson, EM