Principal Supervisor: Prof John Schwabe - Department of Molecular and Cell Biology
Co-supervisor: Dr. Shaun Cowley
PhD project title: Cryo-Electron Microscopy of Histone Deacetylase Complexes
University of Registration: University of Leicester
Crystal structure of HDAC1:MTA1 with InsP6 bound at the interface between the two proteins. The HDAC inhibitor, a modified histone H4 peptide H4K16Hx (pink), is bound to the active site (Watson 2016).
Negative stain EM model of the NuRD complex (Millard 2016).
Histone deacetylase complexes play a role in many cellular processes, such as cancer, cell cycle progression and DNA
Class-1 histone deacetylases (HDACs 1, 2, 3) are essential
The Schwabe group have been successful in expressing and
There has recently been a revolution in Cryo-Electron Microscopy, which means that large protein and protein complex structures that previously could not be crystallised can now be solved at atomic resolution. The aim of this PhD project is to solve the structure of histone deacetylase complexes using Cryo-electron microscopy and to fully understand the structure of the different HDAC complexes, their interaction with chromatin and their interaction with other components involved in transcription. An understanding of the structure of the different HDAC complexes may lead to the design of more specific histone deacetylase inhibitors.
- Millard CJ, Varma N, Saleh A, Morris K, Watson PJ, Bottrill AR, Fairall L, Smith CJ & Schwabe JW (2016) The structure of the core NuRD repression complex provides insights into its interaction with chromatin. eLife 5: e13941
- Watson PJ, Millard CJ, Riley AM, Robertson NS, Wright LC, Godage HY, Cowley SM, Jamieson AG, Potter BVL & Schwabe JWR (2016) Insights into the activation mechanism of class I HDAC complexes by inositol phosphates. Nature Communications 7: 11262
- Itoh T, Fairall L, Muskett FW, Milano CP, Watson PJ, Arnaudo N, Saleh A, Millard CJ, El-Mezgueldi M, Martino F & Schwabe JWR (2015) Structural and functional characterization of a cell cycle associated HDAC1/2 complex reveals the structural basis for complex assembly and nucleosome targeting. Nucleic Acids Res 43: 2033–2044
- Hudson GM, Watson PJ, Fairall L, Jamieson AG & Schwabe JWR (2015) Insights into the Recruitment of Class IIa Histone Deacetylases (HDACs) to the SMRT/NCoR Transcriptional Repression Complex. J Biol Chem 290: 18237–18244
BBSRC Strategic Research Priority: Molecules Cells and Systems
Techniques that will be undertaken during the project:
This project will involve protein cloning, protein expression, purification, western blots, mass spectrometry, proteomics approaches and cryo-electron microscopy. Proteomics approaches and cryo-electron microscopy are techniques that are at the forefront of biological science research.
Contact: Professor John Schwabe, University of Leicester