The G protein-coupled receptor (GPCR) cascade leading to production of the second messenger cAMP is replete with pharmacologically targetable receptors and enzymes with the exception of the stimulatory G protein α subunit, Gαs. GTPases remain largely undruggable given the difficulty of displacing high affinity guanine nucleotides and the lack of other drug binding sites. We explored a chemical library of 1012 cyclic peptides in order to expand the chemical search for inhibitors of this enzyme class. We identified a macrocyclic peptide, GsIN-1, that antagonizes the GTP-bound active state of Gαs with high G protein specificity and nucleotide-binding-state selectivity. A 1.57 Å co-crystal structure reveals that GsIN-1 binds to a novel switch II / α3 pocket in Gαs and directly blocks adenylyl cyclase activation. GsIN-1 inhibits isoproterenol-stimulated Gαs activation through binding to the crystallographically defined pocket. The discovery of GsIN-1 provides a path for the development of state-dependent GTPase inhibitors. ### Competing Interest Statement The authors have declared no competing interest.
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