A GTP-state specific cyclic peptide inhibitor of the GTPase Gαs
A GTP-state specific cyclic peptide inhibitor of the GTPase Gαs
Abstract 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 ? 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 path for the development of state-dependent GTPase inhibitors. One sentence summaryTargeting the previously undruggable ON-state of the GTPase Gαs with a macrocyclic peptide inhibitor.
Suga Hiroaki、Hu Qi、von Zastrow Mark、Zhang Ziyang、Lazar Andre、Gao Rong、Dai Shizhong A.、Shokat Kevan M.
Department of Chemistry, Graduate School of Science, The University of TokyoDepartment of Cellular and Molecular Pharmacology, University of California San Francisco||Howard Hughes Medical InstituteDepartment of Cellular and Molecular Pharmacology, University of California San Francisco||Department of Psychiatry, University of CaliforniaDepartment of Cellular and Molecular Pharmacology, University of California San Francisco||Howard Hughes Medical InstituteDepartment of Cellular and Molecular Pharmacology, University of California San Francisco||Department of Psychiatry, University of CaliforniaDepartment of Chemistry, Graduate School of Science, The University of TokyoDepartment of Cellular and Molecular Pharmacology, University of California San Francisco||Howard Hughes Medical InstituteDepartment of Cellular and Molecular Pharmacology, University of California San Francisco||Howard Hughes Medical Institute
药学生物化学分子生物学
Suga Hiroaki,Hu Qi,von Zastrow Mark,Zhang Ziyang,Lazar Andre,Gao Rong,Dai Shizhong A.,Shokat Kevan M..A GTP-state specific cyclic peptide inhibitor of the GTPase Gαs[EB/OL].(2025-03-28)[2025-05-10].https://www.biorxiv.org/content/10.1101/2020.04.25.054080.点此复制
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