基于结构的雄激素受体基因突变数据库:连接分子定位和受体功能的工具

L. Brive, D. Agus, K. R. Ely
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引用次数: 1

摘要

背景:前列腺癌细胞中出现的雄激素受体(ARs)突变可能直接导致一些患者的晚期疾病发展。因此,对改变受体的结构理解将为导致雄激素非依赖型疾病或转移性扩散的分子触发提供新的信息。方法:认识到AR突变对受体功能的影响需要分子定位,我们使用AR配体结合结构域的结构模型来定位在前列腺癌中发生的该结构域的一组全面突变。取代被分为可能影响(1)配体结合,(2)二聚化,或(3)辅激活剂结合/转激活的取代。结果:结果被制成表格,并用于开发一个新的基于结构的数据库,将前列腺癌细胞中表达的每个突变受体的分子位置与临床观察联系起来。数据库中的分类可以交叉引用,以检索每个突变,替代的分子细节,疾病的临床阶段,治疗史和突变受体的功能表型。结论:该数据库将为开发针对AR的治疗方法和了解AR在雄激素依赖性中的作用提供资源。
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Structure‐Based Androgen Receptor Gene Mutation Database: A Tool to Link Molecular Location and Receptor Function
Background: Mutant androgen receptors (ARs) that arise in prostate cancer cells may contribute directly to the development of advanced disease in some patients. Therefore, a structural understanding of the altered receptors will provide new information about the molecular triggers that lead to androgen-independent disease or metastatic spread. Methods: Recognizing that molecular localization is required to understand the effect of AR mutations on receptor function, a structural model of the ligand-binding domain of AR was used to locate a comprehensive set of mutations in this domain that occur in prostate cancer. Substitutions were grouped into those that are likely to affect (1) ligand binding, (2) dimerization, or (3) coactivator binding/transactivation. Results: The results were tabulated and were used to develop a novel structure-based database linking molecular location with clinical observations for each mutant receptor expressed in the prostate cancer cells. Categories in the database can be cross-referenced to retrieve, for each mutation, molecular details of the substitution, clinical stage of the disease, treatment history, and functional phenotype of the mutant receptor. Conclusions: This database will be a resource for the development of therapeutics targeted to the AR and for understanding the role of ARs in androgen independence.
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