CRYSTALLOGRAPHIC STUDIES OF KEY PROTEINS FROM GLOBAL INFECTIOUS DISEASES

Stanford University, Stanford CA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Hol laboratory is focused on proteins from major global pathogens that are promising targets for the development of much-needed new pharmaceuticals to treat such diseases as malaria, sleeping sickness, leishmaniasis, children?s diarrhea and cholera. A special characteristic of the laboratory is to study proteins and in particular multi-proteins assemblies that are, by themselves, extremely interesting with respect to architecture, function and properties. On the basis of the structures obtained we also aim to obtain high affinity inhibitors. As a result we are investigating three multi-protein assemblies, including (i) the Type 2 Secretion System which exports cholera toxin across the outer membrane of Vibrio cholerae, (ii) the unique U-insertion/deletion RNA editing system in Trypanosomatids, and (iii) the invasion machinery of the malaria parasite. In addition we are studying peroxins, proteins essential for the biogenesis of the unique glycosome organelles in trypanosomes, and carefully selected tRNA synthetases from a variety of pathogenic protozoa which are exciting drug targets. A new development in the lab is the use of single-domain antibodies from camelids, called ?nanobodies?, which in many cases greatly accelerate crystal growth, and also assist in structure determination.