We have demonstrated that a productive GPCR structure pipeline has been established at TSRI and is capable of generating breakthrough results. Based on prior experience, we now need to optimize the feedback loops that exist within the processes, this will result in an increase in efficiency and reduction in the cost of future GPCR structures. Determination of each new GPCR structure remains a costly multistage process with many challenges and requires thorough optimization. Moreover, the impact of structural genomics on understanding GPCR biological function and selectivity hinges on our ability to effectively leverage each high resolution structure solved. This project will be focused on development and application of advanced computational tools to address these needs and improve throughput, success rate, cost-efficiency and overall impact of the structure determination program. Structure-based computer-aided tools for rational protein engineering will be employed to design conformationally stable GPCRs and GPCR-ligand complexes for crystallization. Based on comprehensive bioinformatics platform and learning from accumulated data for the GPCR family, mathematical models will be implemented to streamline selection of experimental conditions for protein expression, purification and crystallization stages. Finally, advanced homology-based 3D conformational modeling and molecular docking will be applied to maximize the impact of each solved GPCR target on understanding of molecular interactions, conformational plasticity and functional selectivity of all GPCRs within the target subfamily, and a complete data package will be distributed to the scientific community.
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