Research Description

Structure-Function Analysis of Proteins
The main objective of our research is to define the relationship between the structure and function of biological macromolecules. Single crystal X-ray diffraction analysis combined with a variety of modern state-of-the-art techniques is used to investigate the structural basis of cellular functions. Research in our laboratory is focused in three main areas:

STRUCTURAL BIOLOGY OF PATHOGENIC PARASITES
Parasitic diseases pose major public health threat worldwide. Research in our laboratory seeks to improve our understanding of the biochemical and biological processes regulating the life cycle of these parasites with the ultimate goal of identifying exploitable drug targets for developing chemotherapeutic strategy. Currently there are three projects under this program.

Folate metabolic pathway of Trypanosoma cruzi.
Trypanosoma cruzi is a protozoan parasite which causes Chagas? disease. The disease affects 16-18 million people and causes 50,000 deaths annually. Despite the enormous global burden of Chagas? disease, no drug is effective in chronic stage and those used for treatment of acute disease result in toxic side effects. With more than 100 million people in 20 countries at risk, yet no hope for a vaccine in the foreseeable future, there is an urgent need for effective chemotherapy for millions of infected individuals. Drugs targeting folate metabolic enzymes have been remarkably successful in the treatment of infectious diseases including parasitic diseases such as malaria. Our research currently focuses on the application of a three dimensional structure-based approach for designing specific and potent inhibitors of T. cruzi dihydrofolate-thymidylate synthase enzyme. Crystal structures of the bifunctional enzyme in complex with substrates and inhibitor have been determined. We have identified a low nanomolar inhibitor of the enzyme as a potent inhibitor of the T. cruzi parasite.

Protein trafficking machinery of Plasmodium falciparum.
Soon after infecting the human host the malaria parasite enters the red blood cells where it multiplies and actively modifies the host cells. Most of the pathophysiological conditions of human malaria caused by P. falciparum are associated with this intraerythrocytic stage. Inside the erythrocyte the parasites are surrounded by three layers of membrane: the parasitophorous vacuole membrane (PVM), the parasites own plasma membrane and the red blood cells own membrane. Yet the parasite encoded proteins are able to transport from inside the parasite all the way to the outer surface of red blood cells. Proteins displayed on the surface of red blood cells are strategically important for the survival of the parasite and of great significance to the disease outcome. Understanding the mechanism of protein trafficking by P. falciparum is therefore of great interest. Our laboratory focuses on the vesicle mediated trafficking machinery of P. falciparum.

STRUCTURE OF BACTERIAL SURFACE PROTEINS AND RECEPTORS
The goal of this program is to elucidate three dimensional structures of bacterial surface proteins and their receptor complexes. Structural information allows us to understand the interaction of these proteins with their receptors and their role in virulence and pathogenesis. This knowledge can be used for designing vaccines and therapeutic tools. One of the projects in this program aims at defining surface epitopes on the pneumococcal surface protein A of Streptococcus pneumonia which is a major virulence factor and a vaccine candidate and elucidating the molecular basis of its recognition and binding to lactoferrin. In the second project in this program we are studying the three dimensional structure of a major virulence factor, Psn, of Yersinia pestis, the causative agent of bubonic plague. This outer membrane protein is a dual receptor for the siderophore, yersiniabactin and for the bacteriocin, pesticin.

STRUCTURAL BIOLOGY OF EMERGING PATHOGENS OF BIODEFENSE SIGNIFICANCE
In this program we are using the structural information from a number of potential drug targets of small pox virus for designing and developing novel chemotherapeutic agents. The targets currently under investigation are deoxyuridine triphosphatase, uracil DNA glycosylase and thymidine kinase. Availability of high resolution structures of these proteins will aid in design and development of specific inhibitors of this key enzyme.