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.
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