Molecular basis of protein-ligand interactions.

点击翻译按钮获取中文摘要

The long-term objective of this research program is to understand the molecular mechanisms and functional consequences of proteins-ligand interactions. We are especially interested in proteins that interact with metal ions and/or other proteins because there are still important gaps in our understanding of how proteins recognize these ligands. Viral proteins are especially well suited for these studies because a single protein frequently harbors many different enzymatic activities and can therefore interact with various ligands. In the current research program, we are focusing on the NS5A protein from the Hepatitis C virus (HCV). We believe that understanding the functions of NS5A could lead to an improved knowledge of HCV infection and viral propagation. A wide variety of metal ions are found in cells. For most proteins, the presence of metal ions is crucial for activity/function. A zinc atom is found in the crystal structure of the NS5A protein and appears critical for both the function of the protein and for viral replication. However, the precise role of this zinc atom in the protein is still unknown and its functional role has not yet received a satisfactory explanation and is still a matter of debate and speculation. While no known enzymatic function has been ascribed to NS5A, it is an essential component of the HCV replicase complex and exerts a wide range of effects on cellular pathways and processes, including innate immunity, host cell growth and proliferation. One of the most exciting areas of research on NS5A is its interactions with host cell proteins and its ability to modulate host pathways. Fortunately, various cellular binding partners have already been identified. We believe that a better understanding of the interactions between NS5A and cellular proteins will reveal key features in the virus-induced modulation of cellular pathways. Our long-term objective for this research program is to understand the molecular determinants that dictate the interactions between enzymes and their ligands, and to understand their functional consequences. To achieve these goals, our current specific objectives are: 1. To characterize the thermodynamic and structural consequences of metal ion binding to the HCV NS5A protein; 2. To characterize the interaction between cellular proteins and the NS5A protein, and their functional consequences. 3. To investigate the ability of NS5A to modulate the expression of cellular genes. Both graduate and undergraduate students will be the driving force in our research program. Through their training in the fields of molecular biology, biochemistry, and structural biology they will continue to make original contributions to the field. Clearly, it is a priority for us to use the NSERC grant to provide excellent training for students interested in rewarding careers in research.