INTRODUCTION Androgen Receptor (AR) plays a pivotal role in the development of male sex and contributes to prostate cancer growth. Different from other nuclear receptors that bind to the co-regulator LxxLL motif in coregulator peptide interaction, the AR Ligand Binding Domain (LBD) prefers to bind to the FxxLF motif. BUD31, a novel co-regulator with FxxLF motif, has been demonstrated to suppress wild-type and mutated AR-mediated prostate cancer growth. METHODS To find out the interaction mechanisms of BUD31 with WT/T877A/W741L AR complex, molecular dynamics simulations were employed to study the complex BUD31 and WT/mutant ARs. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) results demonstrated that T877A and W741L point mutations can reduce the binding affinity between BUD31 and AR. The RMSF and dynamic cross-correlation analysis indicated that amino acid point mutations can affect the motions of loop residues in the AR structure. RESULTS These results indicated that AR co-regulator binding site AF2 can serve as a target for drug discovery to solve the resistance problem.

中文翻译：

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协同调节物BUD31与AR AF2位点结合机理的新见解：结构测定和突变效应分析。

简介雄激素受体（AR）在男性发育中起关键作用，并有助于前列腺癌的生长。与其他在共调节因子肽相互作用中与共调节因子LxxLL基序结合的核受体不同，AR配体结合域（LBD）倾向于与FxxLF基序结合。BUD31是一种具有FxxLF主题的新型协同调节剂，已被证明可以抑制野生型和突变的AR介导的前列腺癌的生长。方法为发现BUD31与WT / T877A / W741L AR复合物的相互作用机理，采用分子动力学模拟方法研究了BUD31与WT /突变AR的复合物。分子力学泊松-玻尔兹曼表面积（MM-PBSA）结果表明，T877A和W741L点突变可降低BUD31与AR之间的结合亲和力。RMSF和动态互相关分析表明，氨基酸点突变可影响AR结构中环残基的运动。结果这些结果表明AR共调节物结合位点AF2可以作为药物发现的靶标来解决耐药性问题。