P-TEFB REGULATORY COMPLEXES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 转录延伸阶段的控制对mRNAs的调控表达至关重要。在启动后不久，大多数RNA聚合酶II分子都会遇到负伸长因素导致的伸长障碍。正转录延伸因子b(P-TEFb)允许聚合酶逃逸并开始有效的延伸。由于控制进入生产性延伸决定了产生全长mRNAs的起始事件的比例，因此P-TEFb的细胞周期蛋白依赖的激酶活性受到与RNA结合蛋白HEXIM1或HEXIM2和SnRNA，7SK形成的三元复合体的高度调控。尽管最近对活性和非活性的P-TEFb复合体进行了生化和功能表征，但调节P-TEFb活性的机制尚不清楚，包括：1)非活性的P-TEFb复合体的组装；2)抑制P-TEFb的活性；3)活性的P-TEFb分子的释放。P-TEFb和P-TEFb相关复合体的高分辨率X射线结构表征有望提供关于转录延长控制机制的大量信息，并可能导致发现治疗心脏肥大、癌症和HIV感染的新药物和治疗方法。本项目的目标是在原子分辨率上阐明调节P-TEFb活性的细胞机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Control of the elongation stage of transcription is critical to the regulated expression of mRNAs. Shortly after initiation most RNA polymerase II molecules encounter a block to elongation caused by negative elongation factors. The Positive Transcription Elongation Factor b (P-TEFb) allows the polymerase to escape and begin productive elongation. Because controlling the entry into productive elongation dictates the fraction of initiation events that produce full length mRNAs, the cyclin dependent kinase activity of P-TEFb is highly regulated by formation of a ternary complex with an RNA binding protein HEXIM1 or HEXIM2 and the snRNA, 7SK. In spite of recent biochemical and functional characterization of the active and inactive P-TEFb complexes, mechanisms regulating P-TEFb activity, including i) assembly of inactive P-TEFb complexes, ii) inhibition of P-TEFb kinase activity, and iii) release of active P-TEFb molecules, are not understood. The high-resolution X-ray structural characterization of P-TEFb and P-TEFb-associated complexes is expected to provide substantial information about transcription elongation control mechanisms and may lead to the discovery of novel drugs and therapies for the treatment of cardiac hypertrophy, cancer and HIV infection. The goal of current project is to elucidate at atomic resolution the cellular mechanisms regulating P-TEFb activity.