A) Example of a MIF crystal structure covalently bound by inhibitor (Figure 1B) at 1.6 Å resolution, PDB 4OSF (1). B) Covalent inhibitor 4-(2-isothiocyanatoethyl)phenol. C) Representative library compounds containing covalent warheads that could be investigated during a student project.
Supervisor: Dr. Fellner (Biochemistry) and Prof. Tyndall/Dr. Vernall (see below)
The Macrophage migratory inhibitory factor (MIF) project is in collaboration with the Tyndall Lab – University of Otago – School of Pharmacy and the Vernall Lab – University of Otago – Department of Chemistry. Co-supervision between the Departments is highly encouraged and will depend on students interest and degree program.
Summary: This project is ideal if you want to use protein crystallography to study small molecule ligand binding at the atomic scale. Together with the Tyndall and Vernall laboratory we are discovering covalent inhibitors for Macrophage migratory inhibitory factor (MIF) and work in the Fellner laboratory would focus on determination of ligand bound protein crystal structures. This is where you come in – you will learn how to create protein crystals and determine the structure of the protein that forms it in complex with ligands. This project also includes measurements at the Melbourne Australian synchrotron (in person or remotely depending on your preference). In addition, you will learn to use several other biochemical techniques to characterise the purified protein. Inhibitor discovery, synthesis and optimisation are also possibilities.
MIF is a pleiotropic cytokine that plays a role in host microbial defence through promotion and maintenance of the inflammatory response. In some disease states, including septic shock, inflammatory arthritis and colitis, MIF activity is maladaptive and contributes to the underlying mechanisms of disease. Future reading, including previously determined ligand bound structures see below.
(1) Tyndall, J. D. A.; Lue, H. Q.; Rutledge, M. T.; Bernhagen, J.; Hampton, M. B.; Wilbanks, S. M., Macrophage migration inhibitory factor covalently complexed with phenethyl isothiocyanate. Acta Crystallogr F 2012, 68, 999-1002. DOI: 10.1107/S1744309112030552.
(2) Spencer, E. S.; Dale, E. J.; Gommans, A. L.; Rutledge, M. T.; Vo, C. T.; Nakatani, Y.; Gamble, A. B.; Smith, R. A. J.; Wilbanks, S. M.; Hampton, M. B.; Tyndall, J. D. A., Multiple binding modes of isothiocyanates that inhibit macrophage migration inhibitory factor. Eur J Med Chem 2015, 93, 501-510. DOI: 10.1016/j.ejmech.2015.02.012.
