Proteins in membranes provide the portals through which membrane-delimited organelles within cells and cells themselves communicate with their external environments. These essential properties make membrane proteins crucial components in biochemistry and in cell biology. Many membrane proteins are involved in processes of disease, and they are the molecular targets of over 40% of all FDA-approved drugs. Atomic level structure informs both biochemical understanding and drug discovery. Yet, whereas membrane proteins constitute 20-30% of all proteins in all of life, results from membrane proteins comprise only 1.6% of atomic structures in the Protein Data Bank. To a large extent, this structural under-representation arises because of the challenges in producing and analyzing membrane protein structure and function. New technology is needed to address these challenges. We propose to develop the Center on Membrane Protein Production and Analysis (COMPPAA, or COMPP for short) as a Biomedical Technology Research Resource (BTRR) for the production and study of membrane proteins of relevance to biology and medicine. We will build on existing facilities and talents at the New York Structural Biology Center (NYSBC), which include capabilities for structure determination by x-ray crystallography, cryo-electron microscopy (cryo-EM) and NMR spectroscopy as well as a facility for high-throughput expression testing and detergent screening for membrane proteins. COMPP will have nine components including four Technology Research and Development (TR&D) projects which will be driven by Driving Biomedical Project (DBP) component that will comprise fifteen selected DBPs to serve as test beds for the TR&D development. TR&D1 will develop technology for the efficient production of recombinant membrane proteins. TR&D2 will develop technology for the optimization of membrane protein samples for structural analysis. TR&D3 will develop generic assays for functional analy
OVERALL ? NARRATIVE Membrane proteins are crucial components of many life processes and the molecular targets of over 40% of all FDA-approved drugs; however, largely because of challenges in producing and analyzing them, membrane proteins are under-represented in structural databases. This Biomedical Technology Research Resource will address the membrane protein challenge with transformative technology. A highly positive impact on human health is likely to be felt from new understanding and new therapeutics that come from having membrane proteins readily available as reagents and structures.
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