Targeting G alpha i/s Proteins with Peptidyl Nucleotide Exchange Modulators

Nubbemeyer, Britta; George, Ajay Abisheck Paul; Kühl, Toni; Pepanian, Anna; Beck, Maximilian Steve; Maghraby, Rahma; Boushehri, Maryam Shetab; Muehlhaupt, Maximilian; Pfeil, Eva Marie; Annala, Suvi Katariina; Ammer, Hermann; Imhof, Diana und Pei, Dehua (2022): Targeting G alpha i/s Proteins with Peptidyl Nucleotide Exchange Modulators. In: ACS Chemical Biology, Bd. 17, Nr. 2: S. 463-473

Abstract

Chemical probes that specifically modulate the activity of heterotrimeric G proteins provide excellent tools for investigating G protein-mediated cell signaling. Herein, we report a family of selective peptidyl G alpha i/s modulators derived from peptide library screening and optimization. Conjugation to a cell-penetrating peptide rendered the peptides cell-permeable and biologically active in cell-based assays. The peptides exhibit potent guanine-nucleotide exchange modulator-like activity toward G alpha i and G alpha s. Molecular docking and dynamic simulations revealed the molecular basis of the protein-ligand interactions and their effects on GDP binding. This study demonstrates the feasibility of developing direct G alpha i/s modulators and provides a novel chemical probe for investigating cell signaling through GPCRs/G proteins.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Tiermedizin > Veterinärwissenschaftliches Department
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1554-8929
• Sprache: Englisch