Professor John Schwabe

Professor of Structural Biology

Profile

Professor John Schwabe’s research spans a number of interrelated areas concerned with understanding enzymes inside the cell nucleus that assemble into large complex molecular machines to regulate genes. His group has led the field in how these complexes are assembled, how they act together with other proteins to control physiology and how this mechanism is affected by disease. During the COVID-19 pandemic the team are using their structural biology expertise to investigate how SARS-CoV-2 gains entry to cells and how this may be targeted with future therapeutics.

The Leicester Institute of Structural and Chemical Biology (LISCB) houses the state-of-the-art £6 million Regional Cryo-Electron Microscopy facility, a revolutionary method to directly visualise the molecular machinery in our cells with atomic-level detail. The microscope is being operated remotely by facility Manager Dr Christos Savva who is working with academic groups and industry partners around the world to investigate how SARS-CoV-2 infects and replicates inside our cells.

Research

  • Structural Biology: NMR Spectroscopy and X-ray Crystallography
  • Molecular mechanisms of the regulation of gene expression
  • Nuclear receptors and their role in metabolism, development and disease

The current major interest in the group is understanding the structure and function of HDAC-containing corepressor complexes. This work is supported by a Wellcome Trust Senior Investigator Award. These complexes play an important role in the regulation of development, differentiation, cancer and homeostasis.

In addition, the group has a long-standing interest in the molecular mechanisms of transcriptional regulation by nuclear receptors. Nuclear receptors are important regulators of gene expression and are major drug targets. Our understanding of the mechanism of the ligand-regulated switch has been greatly enhanced by studies of the structure and dynamics of nuclear receptors.

In addition to these core research areas, the group is also involved in a number of collaborative projects with an emphasis on proteins and complexes implicated in various cancers.

Publications

Fox, J.L., Hughes, M.A., Powley, I.R., Juke-Jones, R., Ragan, T.J., Dinsdale, D., Fairall, L., Schwabe, J.W.R., Morone, N., Cain, K., MacFarlane, M. (2021) Cryo-EM structural analysis of FADD:Caspase-8 complexes defines the catalytic dimer architecture for coordinated control of cell fate. Nature Communications In Press.

Xiao, X., Kim, Y., Romartinez-Alonso, B., Sirvydis, K., Ory, D., Schwabe, J.W.R., Jung, M.E. and Tontonoz, P. (2021) Small molecule Aster inhibitors distinguish vesicular and non-vesicular sterol transport mechanisms. Proceedings of the National Academy of Sciences USA 118, e2024149118.

Turnbull, R., Fairall, L., Saleh, A., Kesall, E., Morris, K., Ragan, T., Savva, C., Chandru, A., Millard, C., Makarvova, O., Smith, C., Rosemann, A., Fry, A., Cowley, S., Schwabe, J.W.R. (2020) The MiDAC histone deacetylase complex is essential for embryonic development and has a unique multivalent structure. Nature Communications 11, 3252.

Millard, C.J., Fairall, L., Ragan, T.J., Savva, C.G. and Schwabe, J.W.R. (2020) The topology of chromatin-binding domains in the NuRD deacetylase complex. Nucleic Acids Research 48, 12972.

Song Y., Dagil l., Fairall L., Robertson N., Wu M., Ragan T.J., Savva G.C., Morone N., Kunze M.B.A., Jamieson A.G., Cole P.A., Hansen D.F., Schwabe J.W.R. (2020) Functional and structural coupling between LSD1 and HDAC1 in the CoREST complex. Cell Reports 30, 2699-2711.

Wang, Z.A., Millard, C.J., Lin, C-L., Gurnett, J., Wu, M., Lee, K., Fairall, L., *Schwabe, J.W.R., *Cole, P.A. (2020) Diverse Nucleosome Site-Selectivity Among Histone Deacetylase Complexes. eLife 9, e57663. *Co-corresponding authors

Smalley, J., Adams, G., Millard, C., Song, Y., *Schwabe, J.W.R., *Cowley, S., *Hodgkinson, J. (2020) PROTAC mediated degradation of Class-I histone deacetylase enzymes in corepressor complexes. Chemical Communications doi: 10.1039/d0cc01485k. *Co-corresponding authors

Williams, G.M., Paschalis, V., Ortega, J., Muskett, F.W., Hodgkinson, J.T., Li, G-M., Schwabe, J.W.R. and Lahue, R.S. (2020) HDAC3 deacetylates the DNA mismatch repair factor MutSb to stimulate triplet repeat expansions. Proceedings of the National Academy of Sciences USA 117, 23597.

Moran, C., Seger, C., Taylor, K., Oddy, O., Burling, K., Rajanayagam, O., Fairall, L., McGowan, A., Lyons, G., Halsall, D., Gurnell, M., Schwabe, J., Chatterjee, K., Strey, C. (2020) Hyperthyroxinemia and hypercortisolemia due to familial dysalbuminemia. Thyroidhttps://doi.org/10.1089/thy.2020.0315.

Freeman S.L., Portolano N., Parkin G., Girija U.V., Kwon H., Basran J., Fielding A.J., Fairall L., Svistunenko D.A., Moody P.C.E., Schwabe J.W.R., Kyriacou C.P. and Raven E.L. (2019) Heme Binding to human CLOCK affects interactions with the E-box. Proceedings of the National Academy of Sciences USA 116, 19911.

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