State-selective modulation of heterotrimeric Gαs signaling with macrocyclic peptides.

Autor:	Dai SA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA., Hu Q; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA., Gao R; Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan., Blythe EE; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA., Touhara KK; Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA., Peacock H; Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan., Zhang Z; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA., von Zastrow M; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA., Suga H; Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: hsuga@chem.s.u-tokyo.ac.jp., Shokat KM; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: kevan.shokat@ucsf.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2022 Oct 13; Vol. 185 (21), pp. 3950-3965.e25. Date of Electronic Publication: 2022 Sep 27.
DOI:	10.1016/j.cell.2022.09.019
Abstrakt:	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 Gα 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 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 Gαs, respectively. Both macrocyclic peptides fine-tune Gαs 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/α3 pocket. Cell-permeable analogs of GN13 and GD20 modulate Gαs/Gβγ signaling in cells through binding to crystallographically defined pockets. The discovery of cyclic peptide inhibitors targeting Gαs provides a path for further development of state-dependent GTPase inhibitors. Competing Interests: Declaration of interests S.A.D., Q.H., R.W., H.P., H.S., and K.M.S. are inventors on patent applications jointly owned by University of Tokyo and UCSF. S.A.D., Q.H., R.W., H.P., H.S., and K.M.S. own shares in G-Protein Therapeutics, a subsidiary of Bridge Bio. K.M.S. has consulting agreements with the following companies, which involve monetary and/or stock compensation: Revolution Medicines, Black Diamond Therapeutics, BridGene Biosciences, Denali Therapeutics, Dice Molecules, eFFECTOR Therapeutics, Erasca, Genentech/Roche, G-Protein Therapeutics, Janssen Pharmaceuticals, Kumquat Biosciences, Kura Oncology, Mitokinin, Nested, Type6 Therapeutics, Venthera, Wellspring Biosciences (Araxes Pharma), Turning Point, Ikena, Initial Therapeutics, Vevo, Rezo, and BioTheryX. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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