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Postdoctoral Position available in the Laboratory of Wim Hol Department of Biochemistry, School of Medicine, University of Washington, Seattle, USA Structural Biology and structure-based inhibitor design of the invasion machinery of the malaria parasite. JOB DESCRIPTION: This project aims to unravel the structure of the invasion machinery of the malaria parasite and to design inhibitors to interfere with the proper functioning of the machinery. Such inhibitors might be the foundation for new anti-malarials. The malaria parasite invades two types of cells when in the human host: hepatocytes and erythrocytes. This invasion is a fascinating and very complex process, but some features are shared in the invasion of these two different cell types. These include aldolase (yes, the glycolytic enzyme is moonlighting here...) interacting with an actin filament, a specific myosin motor interacting with the actin, a myosin-tail interacting protein (MTIP), and a number of so-called GAP proteins. We have elucidated several structures of interacting proteins in this system. There are also exciting invasion-blocking compounds which we try to co-crystallize with their target protein. The aims for the project in the next few years are; (i) to obtain additional structural information about additional proteins and multi-protein complexes of the machinery; and, (ii) to assist in structure-based design of invasion inhibitors. The project is an interdisciplinary collaboration with molecular modeling, chemical synthesis, parasitolology and biochemical groups, in the Biomolecular Structure Center of the University of Washington, Seattle, and Drexel University, Philadelphia. The successful candidate will have the opportunity to: (i) carry out protein expression and protein chemistry studies to obtain insight into protein-protein interactions involving the invasion machinery of the malaria parasite; (ii) determine high resolution crystal structures of individual proteins as well as multi-protein sub-complexes of the machinery; (iii) solve crystal structures of invasion proteins in complex with small molecule inhibitors. There will also be opportunities to carry out biophysical binding assays. Several expression systems are already available for preparing soluble proteins from the invasion machinery. For further information regarding our studies on the invasion machinery see: Bosch, J., Turley, S., Daly, T. M., Bogh, S. M., Villasimil, M. L., Roach, C., Zhou, N., Morrisey, J. M., Vaidya, A. B., Bergman, L. W. & Hol, W. G. J. (2006). Structure of the Plasmodium MTIP-MyoA complex, a key component of the malaria parasite invasion motor. Proc. Natl. Acad. Sci. USA 103, 4852-4857. Bosch, J., Buscaglia, C. A., Krumm, B. E., Ingason, B., Lucas, R., Roach, C., Cardozo, T., Nussenzweig, V. & Hol, W. G. (2007). Aldolase provides an unusual binding site for TRAP in the invasion machinery of the malaria parasite. Proc. Natl. Acad. Sci. USA, 104, 7015-8020. Bosch, J., Turley, S., Roach, C., Daly, T. M., Bergman, L. W. & Hol, W. G. (2007) The Closed MTIP-MyosinA-tail Complex from the Malaria Parasite Invasion Machinery. J Mol Biol. 372, 77-88. And for information regarding the research in our lab see the websites: http://www.bmsc.washington.edu/WimHol/ http://depts.washington.edu/biowww/faculty/hol.html JOB REQUIREMENTS: - Experience with: - protein expression and purification methods - characterization of purified soluble proteins - protein crystallization - At least three years of experience with protein structure determination methods, including: X-ray diffraction data collection and data processing; experimental and molecular replacement phasing methods; density modification; crystallographic refinement. - Excellent interpersonal skills to function optimally in the malaria invasion project team and to cooperate with collaborators in other groups and institutions. Experience in one or more of the following fields would be a plus: - Molecular biology for protein overexpression - Purification and characterization of multi-protein complexes - Biophysical binding assays - Molecular modeling for inhibitor design. START DATE: Immediately INSTITUTION: Department of Biochemistry Biomolecular Structure Center School of Medicine Box 357742 University of Washington Seattle, WA, 98195 USA Please send your CV, including a description of your experience, a list of publications, and names and email addresses of three references able to assess your scientific experience and capabilities to: [log in to unmask]