Resolving the mechanism of specific G-protein inhibitors by NMR spectroscopy

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One possibility to disentangle the multiplicity of receptor-G protein interactions is to apply G-protein-specific inhibitors. So far, such inhibitors are rare but the depsipeptide FR900359 has been shown to act in a highly selective way onto the α-subunit of the G-Protein Gq. It also diminishes the activity of oncogenic Gqα mutants. Many details of the key step of the G-protein cycle, namely GDP/GTP exchange, and the mechanism of action of FR900359 remain to be resolved. Here, mainly solid-state NMR spectroscopy will be used to analyse Gqα in the membrane context by characterizing the mode of nucleotide binding, by analysing the intrinsic GTPase activity and by describing protein structure and dynamics in response to FR900359. The study will be expanded towards specific mutants, which are constitutively active and are considered as oncogenic drivers for various cancers.