PRISM has a strong structural biology research group with broad range of interests.
Dr. Cygler laboratory is interested in structural aspects of protein-protein interactions, protein complexes and protein-carbohydrate interactions. The goal is to provide molecular basis for understanding the processes underlying bacterial infection and, in particular, the interaction between bacterial pathogens and their host, emphasizing the invasiveness and survival within host macrophages and epithelial cells. Structural biology plays an essential role in attaining this level of understanding and translating the macroscopic view of host-pathogen interactions into a three-dimensional picture of molecules in action. We apply our well established structure determination pipeline and expertise in protein-protein interactions to the investigation and characterization of intracellularly injected proteins (effectors) and their interactions with host proteins. Our methodology is ideally suited to investigate host-pathogen interactions at the molecular level. We will pursue functional roles of effectors, their interactions with host proteins and three-dimensional structures of the effectors and effector-target complexes essential for bacterial virulence.
Dr. Grochulski ‘s main scientific interest is the application of synchrotron radiation to structural biology and includes: structure-function relationships of biological molecules, mechanisms of enzymatic activities (including stereoselective enzymatic reactions), rational drug design and drug delivery systems as well as biological membranes. Additionally, he pursues the development of synchrotron instrumentation and methodology. This includes refinement of synchrotron-based phase determination techniques, especially related to macromolecular crystallography (MX), as well as small molecule crystallography, powder diffraction, and small angle X-ray scattering (SAXS).
In a healthy cell, most proteins fold into a specific structure or conformation soon after they are synthesized. When the protein is no longer needed then it is broken down and the amino acid building blocks are reused to make new proteins. Under certain pathological conditions, the normal process of synthesis and renewal malfunctions and misfolded proteins can begin to accumulate. Misfolded proteins are unusual because they are difficult to degrade and eventually their presence interferes with critical cell functions and the cell dies. The misfolded proteins often aggregate into “amyloid plaques” which can be identified under a microscope. The presence of amyloid plaques in the brain is the hallmark of many neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Although the proteins which cause the disease are well known, the reasons why they misfold are not well understood.
Dr. Lee research program is funded by NSERC and the Parkinson’s Society. He is using nanopore analysis to study the folding and misfolding of proteins. In this technique, a small pore of nanometre dimensions is inserted into a membrane and when a voltage is applied across the pore a current will flow. If a small protein enters the pore then the current will be blocked for as long as a microsecond and this event can be detected electronically. His team has found that the signal caused by the protein is very sensitive to its precise conformation as it enters the pore. Thus they are able to gather detailed structural information, which is difficult by other techniques. For example, they have discovered that a-synuclein which is involved in Parkinson’s folds into a stable conformation upon binding nicotine. This may explain why cigarette smokers have a reduced risk for developing the disease. In the long term, this knowledge may lead to the development of drugs, which could be used to treat neurodegenerative and other protein misfolding diseases.
Dr. Leung is a new investigator at the Department of Veterinary Biomedical Sciences at WCVM. Dr. Leung is interested to understand how protein complexes implicated in psychiatric diseases function in neurodevelopment. The Leung lab employs a unique combination of molecular and in vivo experimental approaches to tackle this problem. Utilizing structural biology to elucidate the atomic details of protein-protein interactions and Drosophila as a tool to unravel their cellular function in an intact nervous system, Dr. Leung strives to integrate structural information with in vivo data to understand the biological functions of these complexes in neurodevelopment.
Dr. Luo is studying three dimensional structures, biochemical properties and inhibition of RecA-like proteins in microorganisms and its seven homologs in human. These proteins are essential for cell survival due to their pivotal role in repairing double-stranded DNA breaks. On the other hand, RecA protein is key factor in rendering pathogenic bacteria resistant to antibiotics, while RecA homologs in human is contributing to cancer cell’s resistance to radio- and chemo-therapies. Crystal structures of these proteins determined using synchrotron X-ray source at the Canadian Light Source will shed light on the mechanism of RecA-like proteins and potentially lead to novel therapies.
Work in Dr Moore's laboratory is focused on understanding protein function using biochemical and structural techniques including protein structure determination by X-ray crystallography. One ongoing project is the investigation of the flagellum specific export apparatus in the human pathogen Helicobacter pylori. Another major research focus is the study of histone acetyltransferase complexes and chromatin targeting molecules.
The Palmer lab studies enzyme catalyzed reactions, with a particular interest in enzymes with unknown or poorly-understood function. Understanding enzyme mechanisms will allow us and others to predict the function of other enzymes, modify enzymes to generate new catalysts, and design inhibitors that can serve as medicinal agents. We teach and apply skills in organic synthesis, molecular biology, protein purification, reaction kinetics, and biophysical chemistry. Although we maintain an interest in any biological reaction mechanism, we are particularly focused on enzymes considered antimicrobial targets, enzymes that produce antibiotics, and in the bioorganic chemistry of inositol.
Dr. Sanders’ research program is focused on understanding how proteins function, by studying their atomic resolution structures. Using protein X-ray crystallography as a tool for elucidating structures, we combine structural studies with enzymology, site-directed mutagenesis and computer-aided design of inhibitors to understand how proteins function. The determination of the 3-D structures of proteins and their complexes enable us to answer important questions about how these proteins function, and how they interact with their substrates and each other.
We are currently studying enzymes that are critical for the survival of pathogenic bacteria and combine structural studies with enzymology and in silico design strategies to develop novel inhibitors of these enzymes. Additionally, research is being conducted on basic studies of protein-protein interactions, focussing on the evolutionary basis for how extremophiles maintain recognition.