Computational Chemistry; Drug Design; Structural Biology; X-ray Crystallography; Bioinformatics; Protein Folding
The long-term goal of my research has been to understand the role of key active site residues in the mechanism of molecular recognition among various classes of proteins. The primary focus has been study of folate-dependent enzyme pathways, in particular dihydrofolate reductase (DHFR). These enzymes from pathogenic Pneumocystis species are of interest for the design of selective inhibitors for the treatment of AIDS-related pneumonia. Analysis of the structural data from several classes of protein has revealed a great degree of conformational flexibility for ligand binding that result in novel modes of binding to the same active site. Understanding the role of such flexibility has aided in the design of new scaffolds for inhibitor design. Additionally, my lab has the expertise to carry out the necessary molecular biology experiments to clone, express and purify proteins for crystallographic study using both bacterial and insect cell host systems. We have a long-standing, successful collaboration with the Queener lab to study DHFR, particularly from the opportunistic pathogens Pneumocystis jirovecii (pj) and Pneumocystis carinii (pc), found in man and rats, respectively. Our lab is also studying transthyretin (TTR), the thyroid hormone transport protein, characterizing the human protein bound to inhibitors with potential to stabilize the tetrameric structure and ameliorate the effects of filbril formation. Transthyrtetin from lamprey is of interest as it is thought to be the cross-over species in the change of function from a hydrolase to hormone transport function.
Structural Biology; X-ray Crystallography; Bioinformatics; Proteins and metalloenzymes; Protein Function and Structure
Dr. Edward Snell is a Senior Scientist and Cheif Executive officer at the Hauptman-Woodward Medical Research Institute and faculty at the SUNY University at Buffalo Department of Structural Biology. He is a board member on the International Organization for Biological Crystallization, a member of the MacCHESS (The Macromolecular diffraction facility at Cornell High Energy Synchrotron Source) Advisory Committee and a member of the executive committee for the Stanford Synchrotron Radiation Lightsource users organization. He serves as a reviewer for multiple international Journals and both national and international funding agencies. He is on the American Crystallographic Association Communications Committee and chair-elect of the Biological Macromolecules Scientific Interest Group. His research group uses complementary techniques to extract structural and dynamic information from biological macromolecules. This research includes the development of crystallization methodology and the resulting analysis with an emphasis on high-energy light sources. Other techniques in use include Electron Paramagnetic Resonance and spectroscopy. He is experienced in solution scattering techniques, having organized and taught at both national and international meetings. The Snell laboratory research is supported by NIH, NSF, DoD, and NASA in addition to non-federal sources.
Structural Biology; X-ray Crystallography; Bioinformatics; Genomics and proteomics; Infectious Disease; Microbial Pathogenesis; Molecular and Cellular Biology; Protein Function and Structure; Proteins and metalloenzymes; Virology
The overarching goal of the Umland Lab is to use structural biology combined with biochemical, molecular biology, and genetics to explore important elements of infectious disease. The objective is to both extend the fundamental understanding of how microbial pathogens interact with their respective hosts and to identify new antimicrobial targets and new antimicrobial therapeutics. Two major projects on this theme are on going within the lab. In the first, unrecognized and underexploited potential antimicrobial targets within multi-, extreme, and pan-drug resistant gram-negative bacilli (GNB) are being identified and then characterized using the phenotype of in vivo essentiality. That is, our interest is in genes and their corresponding gene products that are essential for bacterial growth and survival during infection of a host (i.e., in vivo) rather than only essential under ideal laboratory growth conditions (e.g., rich laboratory media, absence of immune responses, etc.). The class of genes that are in vivo essential but not in vitro essential has largely been neglected as antimicrobial targets, and so represents a rich set for expanding target space in the urgent race to develop new antimicrobials. The second project is focused upon identifying and characterizing virus protein - host protein interactions. Viruses encode a highly limited set of functionality, and therefore rely on subverting cellular machinery. This high jacking of cellular functions for the benefit of the virus often involved virus-host protein-protein interactions (PPIs). Study of these virus-host PPIs reveals both the mechanisms by which viruses co-opt cellular functions and potential new antiviral targets recalcitrant to the development of drug resistance. An additional rationale for studying virus-host PPIs is to understand virus evolution with respect to PPI involvement in virulence, pathogenesis, and host tropism. In conjunction with both of these projects, the Umland Lab is using structurally enabled fragment-based lead discovery (FBLD) methods to identify small molecules with potential to be developed into antimicrobial therapeutics.