S1: Case Study in Protein Kinases
Structural Genomics Consortium
Plasmodium parasites boast a kinome with over 90 members, close to half of which are essential and therefore potential drug targets.
They are also all S/T kinases.
Interestingly, we have found a number of inhibitors of human tyrosine kinases to be particularly potent anti-malarial compounds in cell-based assays.
We also found a number of Plasmodium S/T kinases to be sensitive to the same inhibitors.
To understand the mechanism of inhibition, we crystallized these kinases, with some of the inhibitors of interest bound.
The resulting structures inform us on the similarities between these parasite S/T kinases and human tyrosine kinases, and how to design potentially selective anti-malarial kinase inhibitors.
Since 2004, Ray’s group (Structural Parasitology) has become the world leader in the expression, purification, crystallization and chemical screening of parasite proteins. The goal of this research is to produce tools to support anti-parasitic drug discovery as well as to enable other parasitologists in their quest to understand parasite biology and host invasion. The tools produced by Ray’s team include purified recombinant parasite proteins, inhibitors of these proteins and their crystallographic structures, all of which are readily shared with parasitology labs around the world.