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A GTP-state specific cyclic peptide inhibitor of the GTPase Gαs

By Shizhong A. Dai, Qi Hu, Rong Gao, Andre Lazar, Ziyang Zhang, Mark von Zastrow, Hiroaki Suga, Kevan M. Shokat

Posted 27 Apr 2020
bioRxiv DOI: 10.1101/2020.04.25.054080

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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