Conformational mechanisms of lung and liver disease
I am a Clinician Scientist interested in understanding the relationship between disease relevant protein behaviours and disease, to identify new drug targets. My research focuses on diseases mediated by inflammation and fibrosis in the lung and liver where there is major unmet clinical need. We study the effects of disease mutations and environmental stimuli upon protein folding and conformational behaviour in serpinopathies (such as a1-antitrypsin deficiency), using X-ray crystallography, NMR spectroscopy, cryo-EM, and native MS. Subsequently, we dissect downstream mechanisms in cells using cell biology and proteomic methods, relate these to disease biology, and undertake proof-of-principle studies into novel therapeutic strategies.
To study interstitial lung diseases my group now also focuses upon what we term the gal-3-fibrosome: a cell-surface interactome that stabilises pro-fibrotic and injury response mediators and can cluster them spatiotemporally. We are undertaking cell biology and interactomic studies to define direct interactions and validate them for pathophysiological significance. These will be further defined in terms of the high resolution structures of sub-complexes within the gal-3-fibrosome and the conformational behaviour of effector domains using structural and biophysical studies.
The cross-cutting nature of my research and clinical interests provides an interface between LISCB and the NIHR Leicester Biomedical Research Centre (BRC)/Leicester Institute of Lung Health where I am a PI, and with clinical practice. I work as a Consultant in Respiratory Medicine at Glenfield Hospital, Leicester and within the London Alpha-1 Antitrypsin Deficiency Service at the Royal Free Hospital in London. In these roles I am also involved in facilitating clinical research in Leicester and London.
- B Gooptu*, SA Faull*, ELK Elliston* et al (2020) The structural basis for Z α-antitrypsin polymerisation in the liver Science Advances, 20206:eabc1370
Dimeloe S, Rice LV, Chen H, Cheadle C, Raynes J, Pfeffer P, Lavender P, Richards DF, Nyon MP, McDonnell JM, Kemper C, Gooptu B, Hawrylowicz CM. (2019) Vitamin D (1,25(OH)2D3) induces α-1-antitrypsin synthesis by CD4+ T cells, which is required for 1,25(OH)2D3-driven IL-10. J Steroid Biochem Mol Biol.189: 1-9.
- Ronzoni R, et al. (2016) 'Aberrant disulphide bonding contributes to the ER retention of alpha1- antitrypsin deficiency variants.' Human Molecular Genetics, vol. 25. Pp. 642-650
- Nyon MP, et al. (2015) 'An integrative approach combining ion mobility mass spectrometry, X-ray crystallography, and nuclear magnetic resonance spectroscopy to study the conformational dynamics of α1 -antitrypsin upon ligand binding.' Protein Sci, vol. 24. Pp. 1301-1312.
- Nyon MP, et al. (2012) 'Structural dynamics associated with intermediate formation in an archetypal conformational disease.' Structure, vol. 20. Pp. 504-512.
Dr Panayiota Stylianou, Dr Chinar Pathak, Charlie Hitchman.
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