Rheb in Complex with Inhibitor NR1

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The mTORC2 protein complex (not shown) regulates cell metabolism and growth in response to nutrients and growth factors. Aberrant mTORC2 signalling pathways are implicated in the pathogenesis of chronic diseases, including metabolic and neurological disease, autoimmune disorders and various cancers (DOI: 10.1242/jcs.125773). First-generation mTORC2 inhibitors have been of limited success as they also perturb normal mTORC1 signalling within the cell. Crucially, the allosteric activation of mTORC2, and not mTORC1, is dependent on the binding of the GTPase protein Rheb to the mTOR constituent. Pharmacological inhibitors of Rheb have thus been developed as therapeutics for mTORC2-related disease (DOI: 10.1038/s41467-018-03035-z), such as the drug compound NR1 which is represented in the above model as bound to Rheb (PDB: 6BT0). Also highlighted are key residues on Rheb’s switch II domain that contribute to the action of NR1 as a potent and selective mTORC2 inhibitor.