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From Proteopedia
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The G protein-coupled receptor cascade leading to production of the second messenger cAMP is replete with pharmacologically targetable proteins, with the exception of the Galpha subunit, Galphas. 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 10(12) cyclic peptides to expand the chemical search for inhibitors of this enzyme class. We identified two macrocyclic peptides, GN13 and GD20, that antagonize the active and inactive states of Galphas, respectively. Both macrocyclic peptides fine-tune Galphas activity with high nucleotide-binding-state selectivity and G protein class-specificity. Co-crystal structures reveal that GN13 and GD20 distinguish the conformational differences within the switch II/alpha3 pocket. Cell-permeable analogs of GN13 and GD20 modulate Galphas/Gbetagamma signaling in cells through binding to crystallographically defined pockets. The discovery of cyclic peptide inhibitors targeting Galphas provides a path for further development of state-dependent GTPase inhibitors. | The G protein-coupled receptor cascade leading to production of the second messenger cAMP is replete with pharmacologically targetable proteins, with the exception of the Galpha subunit, Galphas. 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 10(12) cyclic peptides to expand the chemical search for inhibitors of this enzyme class. We identified two macrocyclic peptides, GN13 and GD20, that antagonize the active and inactive states of Galphas, respectively. Both macrocyclic peptides fine-tune Galphas activity with high nucleotide-binding-state selectivity and G protein class-specificity. Co-crystal structures reveal that GN13 and GD20 distinguish the conformational differences within the switch II/alpha3 pocket. Cell-permeable analogs of GN13 and GD20 modulate Galphas/Gbetagamma signaling in cells through binding to crystallographically defined pockets. The discovery of cyclic peptide inhibitors targeting Galphas provides a path for further development of state-dependent GTPase inhibitors. | ||
| - | State-selective modulation of heterotrimeric Galphas signaling with macrocyclic peptides.,Dai SA, Hu Q, Gao R, Blythe EE, Touhara KK, Peacock H, Zhang Z, von Zastrow M, Suga H, Shokat KM Cell. 2022 Oct 13;185(21):3950-3965.e25. doi: 10.1016/j.cell.2022.09.019. Epub, 2022 Sep 27. PMID:36170854<ref>PMID:36170854</ref> | + | State-selective modulation of heterotrimeric Galphas signaling with macrocyclic peptides.,Dai SA, Hu Q, Gao R, Blythe EE, Touhara KK, Peacock H, Zhang Z, von Zastrow M, Suga H, Shokat KM Cell. 2022 Oct 13;185(21):3950-3965.e25. doi: 10.1016/j.cell.2022.09.019. Epub , 2022 Sep 27. PMID:36170854<ref>PMID:36170854</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
Crystal structure of GDP-bound GNAS in complex with the cyclic peptide inhibitor GD20
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