Multifunctional molecular machines acting on DNA: the XPD and XPB helicases. (360G-Wellcome-091825_Z_10_Z)

Helicases are molecular machines that unwind and remodel DNA and RNA in a wide variety of essential cellular processes. To understand helicase function, we need to understand their molecular structures and the dynamic conformational changes central to their catalytic mechanisms. The DNA helicases XPD and XPB are the enzymatic components of the transcription factor TFIIH and are essential for the fundamental cellular processes of Nucleotide Excision Repair (NER) and transcription initiation. Euka ryal TFIIH is difficult to study at a molecular level and the archaeal homologues of XPD and XPB have proven to be important model systems. Building on our long track record studying the archaeal enzymes, we have brought together a number of cutting-edge technologies including crystallography, biochemistry, genetics, single molecule assays, EPR and biophysics. We aim to determine the structural changes inherent in XPD and XPB action, define the function of domains such as the Fe-S cluster domain of XPD and Thumb domain of XPB and gain an understanding of their mechanisms at a molecular level. These studies will provide valuable new insights relevant to human health and disease and provide an enhanced understanding of an important class of enzymes fundamental to human biology.