• 1988 - B.Sc. in Physics, Beijing University, China
• 1995 - Ph.D. in Physics, SUNY @ Stony Brook, USA
• 1995 - 1997 postdoctoral fellow, Harvard University
• 1997 - 2000 postdoctoral Fellow, Cancer Research UK
• 2001 - 2005 Lecturer, Imperial College London
• 2005 - 2008 Reader, Imperial College London
• 2007 - visiting professor, college of life sciences, Peking University, China

Research

My research programme focuses on unravelling the mechanisms of macromolecular machines using a range of structural biology techniques including X-ray crystallography and cryo-electron microscopy. I am particularly interested in the large AAA (ATPase Associated with diverse cellular Activities) protein family that convert the energy from ATP hydrolysis into mechanical forces required for a myriad of biological pathways. At present my research focuses on two main areas: transcriptional regulation in bacteria and the role of p97 in mammalian organelle biogenesis. In bacteria, transcription of many stress related genes is regulated by specialised activator proteins, which interact directly with the complex between RNA polymerase and sigma54 factor. We are interested in the  mechanism of gene activation carried out by this class of activators through the hydrolysis of ATP. My research has recently expanded to investigate other transcription regulatory networks, in particular those involved in antibiotic resistance. My second area of research is on p97, an abundant cellular protein involved in a diverse range of cellular activities through the coordination with accessory proteins.

Transcription regulation - One of my main research areas is to understand the transcription regulation, in particular the activation/initiation process. We use the bacterial sigma54 dependent system as a simplified model system to establish the structural basis for the transcription initiation, in particular how double stranded DNA is melted out and template strand delivered into the activate site of RNA polymerase. This project is in collaboration with Prof. Martin Buck FRS, Imperial College and Prof Ray Dixon FRS, John Innes Centre. Recently we have also initiated studies in other aspects of transcription such as elongation in collaboration with Dr. Katsu Murakami, Penn State University.

Gene regulation involved in antibiotic resistance -  One of the mechanisms bacteria utilised in antibiotic resistance is to actively extrude antibiotics from bacterial cells through membrane bound efflux pumps. The expression of these pumps is highly regulated. Understanding the detailed mechanism of the controlled expression could therefore offer alternative avenues to combat bacterial antibiotic resistance. We have been studying the structure and regulation of a set of transcription regulators involved in controlling the efflux pumps in gram negative bacteria. This project is collaboration with Prof. Juan Ramos and Dr. Mari-Trini Gallegos, Granada, Spain.

 Structure and mechanism of AAA ATPases p97 - p97 is an abundant protein which has been reported to be involved in a myriad of cellular activities including formation of golgi, ER and the nuclear envelope as well as ER associated protein degradation (ERAD). Mutations in p97 have been linked to various diseases and p97 is shown to interact with over 40 protein partners. We are studying the mechanism of p97 and its interactions with a diverse range of cofactors. This is a joint project with Prof. Paul Freemont, Imperial College London.

Selected recent publications

Klein BJ, Bose D, Baker KJ, Yusoff ZM,  Zhang X*, Murakami KS*. “The RNA polymerase and transcription elongation factor Spt4/5 complex structure”  Proc. Nat. Acad. Sci. USA. Online publication, Dec 27, 2010.

 Lu D, Fillet S, Meng C, Alguel Y, Kloppsteck P, Bergeron L, Krell T, Gallegos, MT, Ramos J, Zhang X (2010). "Crystal structures of TtgV in complex with its DNA operator reveals a general model for cooperative DNA binding of tetrameric gene regulators". Genes Dev. 24(22):2556-65.

Tucker NP, Ghosh T, Bush M, Zhang X* and Dixon R* (2009). "Essential roles of three enhancer sites in σ⁵⁴-dependent transcription by the nitric oxide sensing regulatory protein NorR". Nucleic Acids Res. 38:1182-1194.

Bose D, Pape T, Burrows PC, Rappas M, Wigneshweraraj SR, Buck M, Zhang X. (2008). “Organisation of an activator bound RNA polymerase holoenzyme”. Molecular Cell, 32(3):337-346.

Zhang X*, Wigley DB*. (2008). “The ‘glutamate switch’ provides a link between ATPase activity and ligand binding in AAA+ proteins”. Nat Struct Mol Biol. 15(11):1223-7.

Alguel Y, Meng C, Teran W, Krell T, Ramos JL, Gallegos MT, Zhang X. (2007) ".Crystal Structures of Multidrug Binding Protein TtgR in Complex with Antibiotics and Plant Antimicrobials" . J Mol Biol. 369(3):829-40.

Pye, V., Beuron F., Keetch, C., Mckeown, C., Robinson CV., Zhang X*., and Freemont P.* (2007) “ The p97-Ufd1-Npl4 Complex: First Sructural Insights”. Proc. Natl. Acad  Sci  USA. 104(2):467-72.

Beuron F., Dreveny I., Yuan X., Pye VE., Mckeown C., Briggs LC., Cliff MJ., Kaneko Y., Wallis R., Isaacson EL, Ladbury JE, Matthews SJ, Kondo H., Zhang X., Freemont PS (2006). “Long range conformational changes in the AAA ATPase p97-p47 adaptor complex” EMBO J 25(9):1967-76

Rappas, M., Schumacher, J., Niwa, H., Buck, M., and Zhang, X. (2006). “Structural basis of nucleotide driven conformational changes in the AAA+ domain of transcriptional activator PspF". J Mol Biol, 357(2):481-92

Rappas M., Schumacher J., Beuron F., Niwa H., Bordes P., Wigneshweraraj SR., Keetch CA, Robinson CV., Buck M., and Zhang X. (2005). "Structural Insights into the Activity of Transcriptional Enhancer-Binding Protein". Science, 307:1972-5.

Dreveny, I., Kondo, H., Shaw, T., Uchiyama, K., Zhang, X., and Freemont, P.S..(2004) “Structural Basis of the interaction between the AAA ATPase p97/VCP and its adaptor protein p47” EMBO J. 23: 1030-1039

Zhang X.,  Shaw A., Bates P., Newman R, Gowen B, Orlova E, Gorman M, Kondo H, Dokurno P, Lally J, Leonard G, Meyer H, van Heel M and Freemont PS, (2000) “Structure of the AAA ATPase p97” Molecular Cell, 6, 1473-1484

*joint corresponding author

For more information, visit my group web page on Freemont/Zhang Group