Communication between the Ligand-Binding Pocket and the Activation Function-2 Domain of Androgen Receptor Revealed by Molecular Dynamics Simulations

doi:10.1021/acs.jcim.8b00796

	Communication between the Ligand-Binding Pocket and the Activation Function-2 Domain of Androgen Receptor Revealed by Molecular Dynamics Simulations
	Hou, Tingjun 3,4,5; Li, Youyong 5; Yu, Huidong 1; Li, Dan 4; Liu, Hui 4; Sun, Huiyong 4; Zhou, Wenfang 4; Kong, Xiaotian 4; Wang, Xuwen 4; Duan, Mojie 2
刊名	JOURNAL OF CHEMICAL INFORMATION AND MODELING
	2019-02-01
卷号	59 期号:2 页码:842-857
ISSN号	1549-9596
DOI	10.1021/acs.jcim.8b00796
英文摘要	Androgen receptor (AR), as a member of the nuclear receptor (NR) superfamily, regulates the gene transcription in response to the sequential binding of diverse agonists and coactivators. Great progress has been made in studies on the pharmacology and structure of AR, but the atomic level mechanism of the bidirectional communications between the ligand-binding pocket (LBP) and the activation function-2 (AF2) region of AR remains poorly understood. Therefore, in this study, molecular dynamics (MD) simulations and free energy calculations were carried out to explore the interactions among water, agonist (DHT) or antagonist (HFT), AR, and coactivator (SRC3). Upon the binding of an agonist (DHT) or antagonist (HFT), the LBP structure would transform to the agonistic or antagonistic state, and the conformational changes of the LBP would regulate the structure of the AF2 surface. As a result, the binding of the androgen DHT could promote the recruitment of the coactivator SRC3 to the AF2, and on the contrary, the binding of the antagonist HFT would induce a perturbation to the shape of the AF2 and then weaken its accommodating capability of the coactivators with the LXXLL motif. The simulation results illustrated that the DHT-AR binding affinity was enhanced by the association of the coactivator SRC3, which would reduce the conformational fluctuation of the AR-LBD and expand the size of the AR LBP. On the other hand, the coactivator-to-HFT allosteric pathway, which involves the SRC3, helix 3 (H3), helix 4 (H4), the loop (L1-3) between helix 1 (H1) and H3, and HFT, was characterized. The HFT's skewness and different interactions between HFT and the LBP were observed in the SRC3-present AR The mutual communications between the AF2 surface and LBP, together with the processes involving the interplay of the ligand binding and coactivator recruitment events, would help in understanding the association of coactivators and rationally develop potent drugs to inhibit the activity of AR.
资助项目	National Key R&D Program of China[2016YFA0501701] ; National Key R&D Program of China[2016YFB0201700] ; National Science Foundation of China[21575128] ; National Science Foundation of China[81773632] ; Shenzhen City Science & Technology Innovation Program[CYZZ20160525094052606]
WOS关键词	PROSTATE-CANCER ; STRUCTURAL BASIS ; PROTEIN ; BICALUTAMIDE ; MECHANISMS ; ENZALUTAMIDE ; TRANSACTIVATION ; ANTIANDROGEN ; INTERDOMAIN ; SUPERFAMILY
WOS研究方向	Pharmacology & Pharmacy ; Chemistry ; Computer Science
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000459948700021
资助机构	National Key R&D Program of China ; National Key R&D Program of China ; National Science Foundation of China ; National Science Foundation of China ; Shenzhen City Science & Technology Innovation Program ; Shenzhen City Science & Technology Innovation Program ; National Key R&D Program of China ; National Key R&D Program of China ; National Science Foundation of China ; National Science Foundation of China ; Shenzhen City Science & Technology Innovation Program ; Shenzhen City Science & Technology Innovation Program ; National Key R&D Program of China ; National Key R&D Program of China ; National Science Foundation of China ; National Science Foundation of China ; Shenzhen City Science & Technology Innovation Program ; Shenzhen City Science & Technology Innovation Program ; National Key R&D Program of China ; National Key R&D Program of China ; National Science Foundation of China ; National Science Foundation of China ; Shenzhen City Science & Technology Innovation Program ; Shenzhen City Science & Technology Innovation Program
内容类型	期刊论文
源URL	[http://ir.wipm.ac.cn/handle/112942/14204]
专题	中国科学院武汉物理与数学研究所
通讯作者	Hou, Tingjun; Li, Youyong
作者单位	1.Rongene Pharma Co Ltd, Shenzhen 518054, Guangdong, Peoples R China 2.Chinese Acad Sci, Key Lab Magnet Resonance Biol Syst, State Key Lab Magnet Resonance & Atom & Mol Phys, Natl Ctr Magnet Resonance Wuhan,Wuhan Inst Phys &, Wuhan 430071, Peoples R China 3.Zhejiang Univ, State Key Lab CAD&CG, Hangzhou 310058, Zhejiang, Peoples R China 4.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310058, Zhejiang, Peoples R China 5.Soochow Univ, Inst Funct Nano & Soft Mat FUNSOM, Suzhou 215123, Jiangsu, Peoples R China
推荐引用方式 GB/T 7714	Hou, Tingjun,Li, Youyong,Yu, Huidong,et al. Communication between the Ligand-Binding Pocket and the Activation Function-2 Domain of Androgen Receptor Revealed by Molecular Dynamics Simulations[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2019,59(2):842-857.
APA	Hou, Tingjun.,Li, Youyong.,Yu, Huidong.,Li, Dan.,Liu, Hui.,...&Jin, Ye.(2019).Communication between the Ligand-Binding Pocket and the Activation Function-2 Domain of Androgen Receptor Revealed by Molecular Dynamics Simulations.JOURNAL OF CHEMICAL INFORMATION AND MODELING,59(2),842-857.
MLA	Hou, Tingjun,et al."Communication between the Ligand-Binding Pocket and the Activation Function-2 Domain of Androgen Receptor Revealed by Molecular Dynamics Simulations".JOURNAL OF CHEMICAL INFORMATION AND MODELING 59.2(2019):842-857.