This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Heterotrimeric guanine nucleotide-binding regulatory proteins, G proteins relay signals from heptahelical transmembrane G protein coupled receptors (GPCRs) to the cellular interior. GPCRs activate G proteins by inducing the release of GDP from the G? subunit in the activated receptor-protein complex. Despite reports of many crystals structures of various G? subunits, we still lack a detailed understanding of the mechanism of receptor activated nucleotide exchange by the G? subunit. Our project is aimed at elucidating transient steps in the G protein activation pathway. Our general strategy is to obtain crystal structures of G protein mutants that we characterized in vitro and in cell-based assays. In particular, we have identified and characterized an interesting class of mutant G protein alpha subunits with extremely high basal rates of GDP release. These studies are very important to understanding the mechanism of action of various GPCR-targeted drugs and will help us to gain more structural insights into G protein signaling pathways in general.
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