Dr A Marek Brzozowski
01904 328265
Email: marek.brzozowski@york.ac.uk
Career Summary
I studied the structure of human haemoglobin for my PhD at the University of Lodz, Poland. In that period (1977-1980) I provided the first structural evidence of stable forms of semi-oxygenated haemoglobin in the T state (Nature, 1984, 307, 74-76). This work - together with the research of ZS Derewenda and T Skarzynski - initiated protein crystallography in Poland. After some period in Max-Planck-Institute fur Experimentelle Medizin in Gottingen and Poland I moved as the post-doc to York in 1989, joining the Structural Biology Laboratory. I worked here on many different biotechnology and health care oriented projects in collaboration with various industrial partners (e.g. Novo-Nordisk, Novozyme, Merck, BMS). Some of this research resulted in the elucidation of structure and mechanism (interfacial activation) of lipases (Nature, 1990), 343, 767-770, Nature, 1991, 351, 491-497), agonism/antagonism, Selective Estrogen Modulation and phytoestrogen actions on Estrogen Receptor (Nature, 1997, 389, 753-758, EMBO Journal, 1999, 18, 4698-4618, Structure, 2001, 9, 145-153), mechanism of activation of blood clotting Factor VII (PNAS, 1999, 96, 8925-8930), and structural description of one of the main human growth hormones: Insulin-like Growth Factor-1 (Biochemistry, 2002, 41, 9389-9397). I was promoted to a Readership position in 2002 and initiated development of structural biology of membrane proteins in York.
Current Research Interest.
My main research interest is focussed on three different areas: (i) structural endocrinology (structural basis of mechanism of hormone action), (ii) structural biology of membrane proteins, and (iii) development of methods for protein crystallisation.
(i) Structural endocrinology.
IGF-I, Insulin and Insulin Receptor studies. The completion of the structural studies around the Estrogen Receptor Ligand Binding Domain allowed me to focus on the structural and functional relationships between insulin and Insulin-like Growth Factor-1. Despite the high structural similarities of their cores and some cross-binding to the cognate receptors (IR and IGF-R) these hormones express very different actions: metabolism control or a tissue growth. Our efforts here (in collaboration with Professor J Jiracek, Prague) should lead into delineation of structural basis of insulin and IGF-1 functions. We synthesise and determine structures of insulin analogues in order to switch this hormone into IGF-like functional protein. This research is strongly linked with our efforts to obtain a structural insight into Insulin:Insulin Receptor complex.
IGFBP-1. Insulin-like Growth Factor Binding Protein (IGFBP-1) is one of the key players in the regulation of IGF-1 blood/tissue levels. It is uniquely up/down-regulated by several other hormones (e.g. estradiol) and its affinity for IGF-1 is modulated by several phosphorylations of this hormone carrier. We work on the structural role of phosphorylation of the IGFBP-1 in the regulation of its bioavailability.
Autism. Together with Dr B Wrigh (NHS York) we initiated multi-disciplinary studies on the molecular aspects of autism. We have already shown that the current hypotheses about the role of Indolo-acryolic acid (IAG) and mercury in the aetiology of autism are not valid. We currently search for molecular markers of autism and try to identify proteins that may assist the early onset of this medical condition. We want to expand this approach to chronic fatigue syndrome (ME).
Figure 1 Structural hot-spots targets in human insulin and IGF-1
(ii) Membrane proteins.
To extend the palette of biological targets in the YSBL I initiated structural biology work on new membrane proteins. We are currently tackling several membrane proteins with different physicochemical and functional properties: proton pump from vacuole membrane of Arabidopsis thaliana (with Prof D Sanders, Dept of Biology), human Insulin Receptor, membrane proteins involved in the Vancomycin resistance (in collaboration with Dr D Roper, Warwick), calcium pump, lantibiotics and others.
(iii) Development of methods for protein crystallisation.
We have a long standing interest in the facilitation of new techniques and approaches for macromolecule crystallisations. The Clear Strategy Screens we have designed (J Appl Cryst., 2001, 34, 97-101) are in a wide use now, though they have been presented only as one of the many alternative approaches. Currently we are trying to develop new crystallisation media (artificial membranes, analogues of cubic lipidic phases, new amphipoles and precipitants (with Prof DK Smith, York)) for the crystallisation of membrane and challenging proteins. One of the outcomes of this work is the development of new crystallisation micro-plate which allows a hundred fold reduction in use of chemicals, also cutting the crystallisation time from days to hrs. Work on a public implementation of this new crystallisation platform is in progress.
Figure 2 Snapshots through new YSBL crystallisation micro-plate
Selected publications.
- Microscale vapour diffusion for protein crystallization.
J Korczynska, T-C Hu, D K Smith, J Jenkins, R Lewis, T Edwards and A M Brzozowski, ActaCryst D, 2007, D63, 1009-1015. - Is the presence of urinary indolyl-3-acryloylglycine associated with autism spectrum disorder?
B Wright, A M Brzozowski, E Calvert, H Farnworth, D M Goodall, I Holbrook, G Imrie, J Jordan, A Kelly, J Miles, R Smith, J Town, Developmental Medicine and Child Neurology, 2005, 47, 190-192 - The crystal structure of Gankyrin, an oncoprotein found in complexes with cyclin-dependent kinase 4, a 19 S proteasomal ATPase regulator, and the tumor suppressors Rb and p53.
S Krzywda, A M Brzozowski, H Higatshitsuji, J Fujita, R Welchman, S Dawson, R J Mayer, A J Wilkinson, J Biol Chem, 2004, 279, 1541-1545 - Toward the insulin-IGF-I intermediate structures: functional and structural properties of the [TyrB25NmePheB26] insulin mutant.
L Zakova, J Brynda, O Au-Alvarez, E J Dodson, G G Dodson, J L Whittingham, A M Brzozowski, Biochemistry, 2004, 43, 16293-16300 - Structural origins of the functional divergence of human Insulin-like Growth Factor-I and Insulin.
A M Brzozowski, E J Dodson, G G Dodson, G N Murshudov, C Verma, J P Turkenburg, F De Bree, Z Dauter, Biochemistry, 2002, 41, 9389-939 - Clear Strategy Screens for macromolecule crystallisation.
A M Brzozowski & J Walton, J Appl Cryst., 2001, 34, 97-101
