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Molecules

Title:		A Paradigm for Peptide Hormone-GPCR Analyses
Author(s):		Naider F; Becker JM;
Address:		"Department of Chemistry, College of Staten Island, CUNY, 2800 Victory Blvd, Staten Island, NY 10314, USA. Department of Microbiology, University of Tennessee, 610 Ken and Blaire Mossman Building, 1311 Cumberland Avenue, Knoxville, TN 37996, USA"
Journal Title:		Molecules
Year:		2020
Volume:		20200918
Issue:		18
Page Number:		-
DOI:		10.3390/molecules25184272
ISSN/ISBN:		1420-3049 (Electronic) 1420-3049 (Linking)
Abstract:		"Work from our laboratories over the last 35 years that has focused on Ste2p, a G protein-coupled receptor (GPCR), and its tridecapeptide ligand alpha-factor is reviewed. Our work utilized the yeast Saccharomyces cerevisiae as a model system for understanding peptide-GPCR interactions. It explored the structure and function of synthetic alpha-factor analogs and biosynthetic receptor domains, as well as designed mutations of Ste2p. The results and conclusions are described using the nuclear magnetic resonance interrogation of synthetic Ste2p transmembrane domains (TMs), the fluorescence interrogation of agonist and antagonist binding, the biochemical crosslinking of peptide analogs to Ste2p, and the phenotypes of receptor mutants. We identified the ligand-binding domain in Ste2p, the functional assemblies of TMs, unexpected and interesting ligand analogs; gained insights into the bound alpha-factor structure; and unraveled the function and structures of various Ste2p domains, including the N-terminus, TMs, loops connecting the TMs, and the C-terminus. Our studies showed interactions between specific residues of Ste2p in an active state, but not resting state, and the effect of ligand activation on the dimerization of Ste2p. We show that, using a battery of different biochemical and genetic approaches, deep insight can be gained into the structure and conformational dynamics of GPCR-peptide interactions in the absence of a crystal structure"
Keywords:		"Allosteric Regulation Binding Sites Ligands Microscopy, Fluorescence Peptide Hormones/chemistry/*metabolism Protein Binding Protein Domains Receptors, G-Protein-Coupled/chemistry/genetics/*metabolism Saccharomyces cerevisiae/metabolism G protein-coupled r;"
Notes:		"MedlineNaider, Fred Becker, Jeffrey M eng GM22086, GM22087, GM 46520/NH/NIH HHS/ Review Switzerland 2020/09/24 Molecules. 2020 Sep 18; 25(18):4272. doi: 10.3390/molecules25184272"