SIGNAL TRANSDUCTION COMPLEXES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We would like to determine the structure of the effector enzyme of vision, PDE6, by itself and in complex with its activating G-protein, transducin. Cyclic nucleotide phosphodiesterases, PDEs, are key regulatory components of signal transduction pathways, and are major targets of current drugs and those in development. No structures are available for any full-length PDE isozymes, although there are some for isolated domains. The key effector enzyme in the G protein cascade of vision is the cGMP-specific PDE6, genetic deficiencies in which cause blindness in humans and animals. It is a 200 kDa heterotetramer (PDE6¿¿¿¿). It is a lipidated peripheral membrane protein, which forms a lipid-dependent complex with activated G-protein.