P-TEFB REGULATORY COMPLEXES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 转录延伸阶段的控制对于mRNA的调控表达至关重要。 在起始后不久，大多数RNA聚合酶II分子遇到由负延伸因子引起的延伸阻断。 正转录延伸因子B（P-TEF B）允许聚合酶逃逸并开始生产性延伸。 由于控制进入生产性延伸决定了产生全长mRNA的起始事件的分数，P-TEFb的细胞周期蛋白依赖性激酶活性通过与RNA结合蛋白HEXIM 1或HEXIM 2和snRNA 7SK形成三元复合物而高度调节。 尽管最近对活性和非活性P-TEFb复合物进行了生物化学和功能表征，但调节P-TEFb活性的机制，包括i）非活性P-TEFb复合物的组装，ii）P-TEFb激酶活性的抑制，和iii）活性P-TEFb分子的释放，尚不清楚。 P-TEFb和P-TEFb相关复合物的高分辨率X射线结构表征有望提供有关转录延伸控制机制的大量信息，并可能导致发现用于治疗心脏肥大、癌症和HIV感染的新型药物和疗法。目前的项目的目标是阐明在原子分辨率的细胞机制调节P-TEFb的活动。

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.