- 1988 - B.Sc. in Physics, Peking 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 - present, visiting professor, College of Life Sciences, Peking University, China
- 2008 - 2014, Professor of Macromolecular Structure and Function, Imperial College London
- 2014 - present, Professor, Section of Structural Biology, Department of Medicine, Imperial College London
- 2011 - 2014, Director, Centre for Structural Biology, Imperial College london
Please visit Structural Biology Section website
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 large macromolecular assemblies invovled in DNA processing as well as the AAA (ATPase Associated with diverse cellular Activities) protein family. At present my research focuses on three main areas: key components in DNA damage response, transcriptional regulation in bacteria, structrue and mechanism of multifunctional p97.
Structures and Mechanisms of key components in the DNA damage response- DNA is exposed to toxic chemicals, UV and other radiation and consequently tens of thousands of DNA bases are damaged each day in every human cell. Cells have developed sophisticated systems using multi-subunit macromolecular complexes to detect, process and repair this damage in a highly controlled and coordinated fashion. We are currently using a multi-disciplinary approach to provide a molecular understanding of some of the key events including signaling, chromatin remodeling and DNA damage repair itself. This project is in collaboration with Prof. Peter Burgers, Washington University in St Louis, Prof. Dale Wigley FRS and Dr. Stephen West FRS, Cancer Research UK.
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. We are also interested in how this process is controlled by the activator proteins belonging to the large AAA ATPase family and how these activators are regulated by upstream cellular signals. This project is in collaboration with Prof. Martin Buck FRS, Imperial College.
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
Ayala R, Willhoft O, Aramayo RJ, Wilkinson M, McCormack EA, Ocloo L, Wigley DB, Zhang X(2018). “Structure and regulation of the human INO80-nucleosome complex”. Nature. 556(7701):391-395.
Aramayo RJ, Willhoft O, Ayala R, Bythell-Douglas R, Wigley DB and Zhang X (2017). "Cryo-EM structures of the human INO80 chromatin-remodelling complex". Nat. Struct. Mol Biol. epublication Dec 4, 2017. doi:10.1038/s41594-017-0003-7
Glyde R, Ye F, Darbari VC, Zhang N, Buck M and Zhang X (2017). “Structures of RNA Polymerase Closed and Intermediate Complexes Reveal Mechanisms of DNA Opening and Transcription Initiation”. Mol Cell. 67(1):106-116
Yang Y, Darbari VC, Zhang N, Lu D, Glyde R, Wang YP, Winkelman JT, Gourse RL, Murakami KS, Buck M, Zhang X (2015). "Structures of the RNA polymerase-s54 reveal new and conserved regulatory strategies". Science, 349:882-885
Shahid T, Soroka J, Kong EH, Malivert L, McIlwraith MJ, Pape T, West SC, Zhang X (2014) " Structure and mechanism of action of the BRCA2 breast cancer tumor suppressor". Nat. Struct Mol Biol doi: 10.1038/nsmb.2899
Bebeacua C, Forster A, McKeown C, Meyer HH, Zhang X* and Freemont P* (2012). "Distrinct conformations of the protein complex p97-Ufd1-Npl4 revealed by electron cryomicroscopy". Proc. Natl. Acad Sci. USA. 2012. 109(4):1098-103.
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.
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.
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.
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.
*joint corresponding author
Elected Member of the European Molecular Biology Organisation (2016)
Wellcome Trust Senior Investigator (since 2012)
Fellow of the Society of Biology (2011)
Royal Society Wolfson Merit Research Award (2011)
Human Frontier Science Programme Young Investigator Award (2002-2005)
First Recipient of Gertrude Goldhabor Women in Physics Award (1993)
et al., 2005, The TetR family of transcriptional repressors, Microbiology and Molecular Biology Reviews, Vol:69, ISSN:1092-2172, Pages:326-+
et al., 2014, Mutational analysis of dimeric linkers in peri- and cytoplasmic domains of histidine kinase DctB reveals their functional roles in signal transduction, Open Biology, Vol:4, ISSN:2046-2441
et al., 2015, Mutations in RNA Polymerase Bridge Helix and Switch Regions Affect Active-Site Networks and Transcript-Assisted Hydrolysis, Journal of Molecular Biology, Vol:427, ISSN:0022-2836, Pages:3516-3526
et al., 2014, The p97-FAF1 Protein Complex Reveals a Common Mode of p97 Adaptor Binding, Journal of Biological Chemistry, Vol:289, ISSN:0021-9258, Pages:12077-12084
et al., 2014, Inter-ring rotations of AAA ATPase p97 revealed by electron cryomicroscopy, Open Biology, Vol:4, ISSN:2046-2441
et al., 2014, Domain movements of the enhancer-dependent sigma factor drive DNA delivery into the RNA polymerase active site: insights from single molecule studies, Nucleic Acids Research, Vol:42, ISSN:0305-1048, Pages:5177-5190
et al., 2008, Organization of an Activator-Bound RNA Polymerase Holoenzyme, Molecular Cell, Vol:32, ISSN:1097-2765, Pages:337-346
et al., 2006, Structural basis of the nucleotide driven conformational changes in the AAA(+) domain of transcription activator PspF, Journal of Molecular Biology, Vol:357, ISSN:0022-2836, Pages:481-492
Rappas M, Bose D, Zhang X, 2007, Bacterial enhancer-binding proteins: unlocking sigma(54)-dependent gene transcription, Current Opinion in Structural Biology, Vol:17, ISSN:0959-440X, Pages:110-116
et al., 2003, The crystal structure of murine p97/VCP at 3.6 angstrom, Journal of Structural Biology, Vol:144, ISSN:1047-8477, Pages:337-348
et al., 2000, Structure of the AAA ATPase p97, Molecular Cell, Vol:6, ISSN:1097-2765, Pages:1473-1484
et al., 2003, The ATP hydrolyzing transcription activator phage shock protein F of Escherichia coli: Identifying a surface that binds sigma(54), Proceedings of the National Academy of Sciences of the United States of America, Vol:100, ISSN:0027-8424, Pages:2278-2283
et al., 2000, The BRCA1 C-terminal domain: structure and function, Mutation Research - DNA Repair, Vol:460, ISSN:0921-8777, Pages:319-332
Zhang X, Wigley DB, 2008, The 'glutamate switch' provides a link between ATPase activity and ligand binding in AAA plus proteins, Nature Structural & Molecular Biology, Vol:15, ISSN:1545-9985, Pages:1223-1227
et al., 2008, Dissecting the ATP hydrolysis pathway of bacterial enhancer-binding proteins, Biochemical Society Transactions, Vol:36, ISSN:0300-5127, Pages:83-88
et al., 2006, Conformational changes in the AAA ATPase p97-p47 adaptor complex, EMBO Journal, Vol:25, ISSN:0261-4189, Pages:1967-1976
et al., 2008, Insights into adaptor binding to the AAA protein p97, Biochemical Society Transactions, Vol:36, ISSN:0300-5127, Pages:62-67
et al., 2008, Trapping of a transcription complex using a new nucleotide analogue: AMP aluminium fluoride, Journal of Molecular Biology, Vol:375, ISSN:0022-2836, Pages:1206-1211
et al., 2007, Structural insights into the p97-Ufd1-NpI4 complex, Proceedings of the National Academy of Sciences of the United States of America, Vol:104, ISSN:0027-8424, Pages:467-472
et al., 2005, Structural insights into the activity of enhancer-binding proteins, Science, Vol:307, ISSN:0036-8075, Pages:1972-1975
et al., 2008, Analysis of nucleotide binding to p97 reveals the properties of a tandem AAA hexameric ATPase, Journal of Biological Chemistry, Vol:283, ISSN:0021-9258, Pages:13745-13752
et al., 2006, Going through the motions: The ATPase cycle of p97, Journal of Structural Biology, Vol:156, ISSN:1047-8477, Pages:12-28
et al., 2007, Crystal structures of multidrug binding protein TtgR in complex with antibiotics and plant antimicrobials, Journal of Molecular Biology, Vol:369, ISSN:0022-2836, Pages:829-840
et al., 2004, Structural basis of the interaction between the AAA ATPase p97/VCP and its adaptor protein p47, EMBO Journal, Vol:23, ISSN:0261-4189, Pages:1030-1039
et al., 1998, Structure of an XRCC1 BRCT domain: a new protein-protein interaction module, EMBO Journal, Vol:17, ISSN:0261-4189, Pages:6404-6411