Chemistry-School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK.
Newcastle University Centre for Cancer, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK.
Int J Mol Sci. 2023 Jan 9;24(2):1270. doi: 10.3390/ijms24021270.
The androgen receptor (AR) is an important drug target in prostate cancer and a driver of castration-resistant prostate cancer (CRPC). A significant challenge in designing effective drugs lies in targeting constitutively active AR variants and, most importantly, nearly all AR variants lacking the ligand-binding domain (LBD). Recent findings show that an AR's constitutive activity may occur in the presence of somatic DNA mutations within non-coding regions, but the role of these mutations remains elusive. The discovery of new drugs targeting CRPC is hampered by the limited molecular understanding of how AR binds mutated DNA sequences, frequently observed in prostate cancer, and how mutations within the protein and DNA regulate AR-DNA interactions. Using atomistic molecular dynamics (MD) simulations and quantum mechanical calculations, we focused our efforts on (i) rationalising the role of several activating DBD mutations linked to prostate cancer, and (ii) DBD interactions in the presence of abasic DNA lesions, which frequently occur in CRPC. Our results elucidate the role of mutations within DBD through their modulation of the intrinsic dynamics of the DBD-DNA ternary complex. Furthermore, our results indicate that the DNA apurinic lesions occurring in the androgen-responsive element (ARE) enhance direct AR-DNA interactions and stabilise the DBD homodimerisation interface. Moreover, our results strongly suggest that those abasic lesions may form reversible covalent crosslinks between DNA and lysine residues of an AR via a Schiff base. In addition to providing an atomistic model explaining how protein mutations within the AR DNA-binding domain affect AR dimerisation and AR-DNA interactions, our findings provide insight into how somatic mutations occurring in DNA non-coding regions may activate ARs. These mutations are frequently observed in prostate cancer and may contribute to disease progression by enhancing direct AR-DNA interactions.
雄激素受体（AR）是前列腺癌的重要药物靶点，也是去势抵抗性前列腺癌（CRPC）的驱动因素。设计有效药物的一个重大挑战在于靶向组成性激活的 AR 变体，最重要的是，几乎所有缺乏配体结合域（LBD）的 AR 变体。最近的研究结果表明，AR 的组成性活性可能发生在非编码区域内存在体细胞 DNA 突变的情况下，但这些突变的作用仍然难以捉摸。由于对 AR 如何与前列腺癌中经常观察到的突变 DNA 序列结合以及蛋白质和 DNA 内的突变如何调节 AR-DNA 相互作用的分子理解有限，因此靶向 CRPC 的新药的发现受到阻碍。我们使用原子分子动力学（MD）模拟和量子力学计算，集中精力研究：（i）合理化与前列腺癌相关的几种激活 DBD 突变的作用，以及（ii）DBD 在存在碱基缺失的 DNA 损伤时的相互作用，这种损伤在 CRPC 中经常发生。我们的结果通过调节 DBD-DNA 三元复合物的固有动力学来阐明 DBD 内突变的作用。此外，我们的结果表明，雄激素反应元件（ARE）中发生的 DNA 无嘌呤损伤增强了 AR-DNA 的直接相互作用，并稳定了 DBD 同源二聚体化界面。此外，我们的结果强烈表明，那些碱基缺失的损伤可能通过席夫碱在 DNA 和 AR 的赖氨酸残基之间形成可逆的共价交联。除了提供一个解释 AR DNA 结合域内的蛋白质突变如何影响 AR 二聚化和 AR-DNA 相互作用的原子模型外，我们的研究结果还深入了解了发生在 DNA 非编码区域的体细胞突变如何激活 AR。这些突变在前列腺癌中经常观察到，并且可能通过增强 AR-DNA 的直接相互作用来促进疾病进展。
