A partially open conformation of an androgen receptor ligand-binding domain with drug-resistance mutations

IF 1.1 4区 生物学 Q4 BIOCHEMICAL RESEARCH METHODS Acta crystallographica. Section F, Structural biology communications Pub Date : 2023-03-30 DOI:10.1107/S2053230X23002224
Selom K. Doamekpor, Panfeng Peng, Ruo Xu, Liandong Ma, Youzhi Tong, Liang Tong
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Abstract

Mutations in the androgen receptor (AR) ligand-binding domain (LBD) can cause resistance to drugs used to treat prostate cancer. Commonly found mutations include L702H, W742C, H875Y, F877L and T878A, while the F877L mutation can convert second-generation antagonists such as enzalutamide and apalutamide into agonists. However, pruxelutamide, another second-generation AR antagonist, has no agonist activity with the F877L and F877L/T878A mutants and instead maintains its inhibitory activity against them. Here, it is shown that the quadruple mutation L702H/H875Y/F877L/T878A increases the soluble expression of AR LBD in complex with pruxelutamide in Escherichia coli. The crystal structure of the quadruple mutant in complex with the agonist dihydrotestosterone (DHT) reveals a partially open conformation of the AR LBD due to conformational changes in the loop connecting helices H11 and H12 (the H11–H12 loop) and Leu881. This partially open conformation creates a larger ligand-binding site for AR. Additional structural studies suggest that both the L702H and F877L mutations are important for conformational changes. This structural variability in the AR LBD could affect ligand binding as well as the resistance to antagonists.

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具有耐药性突变的雄激素受体配体结合域的部分开放构象
雄激素受体(AR)配体结合域(LBD)的突变可导致对用于治疗前列腺癌的药物产生耐药性。常见的突变包括L702H、W742C、H875Y、F877L和T878A,而F877L突变可将恩杂鲁胺、阿帕鲁胺等第二代拮抗剂转化为激动剂。然而,另一种第二代AR拮抗剂pruxelutamide对F877L和F877L/T878A突变体没有激动作用,反而保持了对它们的抑制活性。本研究表明,四重突变L702H/H875Y/F877L/T878A在大肠杆菌中增加了AR LBD与普鲁卢胺复合物的可溶性表达。与激动剂双氢睾酮(DHT)复合物的四重突变体的晶体结构显示,由于连接螺旋H11和H12的环(H11 - H12环)和Leu881的构象改变,AR LBD的部分开放构象。这种部分开放的构象为AR创造了更大的配体结合位点。另外的结构研究表明,L702H和F877L突变对构象变化都很重要。AR LBD的这种结构变异性可能影响配体结合以及对拮抗剂的抗性。
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来源期刊
Acta crystallographica. Section F, Structural biology communications
Acta crystallographica. Section F, Structural biology communications BIOCHEMICAL RESEARCH METHODSBIOCHEMISTRY &-BIOCHEMISTRY & MOLECULAR BIOLOGY
CiteScore
1.90
自引率
0.00%
发文量
95
期刊介绍: Acta Crystallographica Section F is a rapid structural biology communications journal. Articles on any aspect of structural biology, including structures determined using high-throughput methods or from iterative studies such as those used in the pharmaceutical industry, are welcomed by the journal. The journal offers the option of open access, and all communications benefit from unlimited free use of colour illustrations and no page charges. Authors are encouraged to submit multimedia content for publication with their articles. Acta Cryst. F has a dedicated online tool called publBio that is designed to make the preparation and submission of articles easier for authors.
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