Steve Gamblin

Structural Biology of Disease Processes Laboratory

We study the structure and function of molecules involved in diseases such as influenza, diabetes and cancer. We use x-ray crystallography, single particle techniques and NMR (nuclear magnetic resonance imaging) to determine the three-dimensional structures and dynamics of these molecules. In combination with biochemistry and biophysics, the data help us elucidate the function of relevant proteins and provide information for the development of therapeutic approaches. Our long-term interests encompass three important disease related areas of biomedical research.

Firstly, we are interested in how covalent modifications to histones regulate gene expression through epigenetic mechanisms. In this area we are focused on the chromatin modifications of enzymes, and enzyme-complexes, that add methylation marks to histone lysine side chains. We are particularly interested in determining the mechanisms that drive this exquisitely targeted modification. Increasing evidence points to the perturbation of epigenetic signalling systems in developmental diseases and cancer.

Secondly, we are studying the master regulator of cellular energy homeostasis, AMP-activated protein kinase (AMPK). AMPK is linked to metabolic diseases such as type-2 diabetes and is therefore an important therapeutic target. Using a structural approach, and working closely with colleagues using cellular techniques, we are gaining important insights into the regulation and mechanism of this critical protein complex.

Finally, we are investigating how changes to the structural properties of the major surface glycoproteins (hemagglutinin and neuraminidase) influence the infectivity of different strains of the influenza virus. We are particularly interested in the rapidly evolving receptor binding characteristics of these proteins. This work builds on our collaboration with John Skehel and with John McCauley's group in the World Influenza Centre.

Structure of AMP

Structure of AMP protein kinase (AMPK) in complex with AMP molecules and an activating drug which binds between the Kinase Domain and the Carbohydrate Binding Domain (Xiao et al 2013).

Selected publications

Collins PJ, Vachieri SG, Haire LF, Ogrodowicz RW, Martin SR, Walker PA, Xiong X, Gamblin SJ, Skehel JJ. (2014) Recent evolution of equine influenza and the origin of canine influenzaProc Natl Acad Sci U S A. 111: 11175-11180.

Xiao B, Sanders MJ, Carmena D, Bright NJ, Haire LF, Underwood E, Patel BR, Heath RB, Walker PA, Hallen S, Giordanetto F, Martin SR, Carling D, Gamblin SJ. (2013) Structural basis of AMPK regulation by small molecule activators.  Nature Communications. 4: Article Number 3017.

Xiong X, Martin SR, Haire LF, Wharton SA, Daniels RS, Bennett MS, McCauley JW, Collins PJ, Walker PA, Skehel JJ, Gamblin SJ. (2013) Receptor binding by an H7N9 influenza virus from humans.  Nature 499:496-499

Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV, Carmena D, Jing C, Walker PA, Eccleston JF, Haire LF, Saiu P, Howell SA, Aasland R, Martin SR, Carling D, Gamblin SJ. (2011) Structure of mammalian AMPK and its regulation by ADPNature 472:230-233.

Margueron R, Justin N, Ohno K, Sharpe ML, Son J, Drury WJ 3rd, Voigt P, Martin SR, Taylor WR, De Marco V, Pirrotta V, Reinberg D, Gamblin SJ (2009) Role of the polycomb protein EED in the propagation of repressive histone marks.  Nature 461, 762-767