PDF(Pubmed)
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.
摘要：
雄激素受体(AR)配体结合域(LBD)中的突变可引起对用于治疗前列腺癌的药物的抗性。常见的突变包括L702H，W742C,H875Y,F877L和T878A,而F877L突变可以将第二代拮抗剂如恩杂鲁胺和阿帕鲁胺转化为激动剂。然而,普鲁西鲁他胺,另一种第二代AR拮抗剂，对F877L和F877L/T878A突变体没有激动剂活性,而是保持其对它们的抑制活性。这里,结果表明，四重突变L702H/H875Y/F877L/T878A增加了大肠杆菌中与普鲁克鲁他胺复合物中ARLBD的可溶性表达。与激动剂二氢睾酮（DHT）复合的四重突变体的晶体结构揭示了ARLBD的部分开放构象，这是由于连接螺旋H11和H12（H11-H12环）和Leu881的环的构象变化。这种部分开放的构象为AR产生更大的配体结合位点。其他结构研究表明，L702H和F877L突变对于构象变化都很重要。ARLBD中的这种结构变异性可以影响配体结合以及对拮抗剂的抗性。
