Illustration of CycT1-V107E on the 3D structures of P-TEFb. a) The V107E mutation in CycT1 was positioned on the structure of P-TEFb and AFF4/SEC. It is located on the H4 helix of the cyclin box (pale yellow) and in distance from the AFF4 binding surface and the binding region of CycT1 to Cdk9 (grey) . b) Cyclin T1 mutations were positioned on the N-terminal helices in the cyclin box of the 3D structure of Tat and P-TEFb (Cdk9/CycT1) [18, 30]. The N-terminal CycT1 cyclin fold is in pale yellow, the C-terminal one is in pale cyan, Tat is in red and Cdk9 is in light grey. This structure shows that Tat adopts a structure and the T-loop of the Cdk9. Mutations that abolished Tat transactivation in murine cells are also presented. The V107 residue is indicated in black. c) Model of CycT1-V107E mode of function - CycT1-V107E does not bind Hexim1 and Cdk9, as well as to TAR RNA and 7SK snRNA. However, its binding to Tat and AFF4 is not impaired. As a result, both Tat and SEC are squelched from the HIV promoter, leading to repression of both Tat-independent and Tat-dependent HIV transcription. Significantly, CycT1-V107E allows the dissection of binding surfaces that are involved in either Tat or Hexim1 binding. Moreover, it signifies the importance of SEC for HIV transcription and can serve as a tool to dissect effects of P-TEFb and SEC on either Tat independent and Tat dependent transcription.