This is a proposal to establish a Center for Protein Structure and Function at the University of Arkansas Protein structure and function is a central biomedical research area within structural biology, and is also crucial to the emerging field of structure-based drug discovery and design. The Center will build upon the unique research expertise of our faculty in the areas of X-ray crystallography, solution and solid-state NMR, mass spectrometry, computational chemistry, rapid laser-initiated kinetic analysis, peptide and drug design, and chemical synthesis. While building on current strengths, the establishment of the Center will substantially augment our capabilities in each of these areas, and will allow us to attract new colleagues to joint our efforts. The unique combination of scientific expertise and state-of-the-art instrumentation in the Center will foster new opportunities for collaboration, and will position our faculty to develop innovative approaches to biomedical research problems. The center will support five multi-disciplinary, collaborative research projects involving 8 junior faculty and 5 new faculty who will receive direct NIH COBRE grant support, and 9 senior faculty who will provide expertise in a broad range of techniques needed to study protein structure and function. The Center will provide the junior investigators with the support and mentoring necessary to develop nationally competitive biomedical research careers, and attract funding through the normal NIH grant mechanism. All five research projects will involve a multi-disciplinary, collaborative approach to obtaining a better understanding of the structure and function of biomedically important proteins. Project 1 will focus on protein folding and orientation within membranes, and peptide transport via ABC-type permeases. Applications will include a better understanding of Clostridium infections and development of anti- Clostridium drugs. Project 2 will involve the development of new families of specific protein inhibitors as candidates for new drugs. Current targets include nucleic acid analogues that can bind to the NS3 helicase of the hepatitis C virus. Project 3 will explore new approaches to determining the structures of signal recognizing particles, which facilitate protein targeting. Project 4 will focus on new experimental and theoretical approaches to understanding the principals governing protein folding. Project 5 will utilize powerful new rapid kinetics understanding the principals governing protein folding. Project 5 will utilize powerful new rapid kinetics techniques to obtain a better understanding of energy coupling mechanisms in oxidative phosphorylation.
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