Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors.

Autor:	Foster SR; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: simon.foster@monash.edu., Hauser AS; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: alexander.hauser@sund.ku.dk., Vedel L; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark., Strachan RT; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA., Huang XP; Department of Pharmacology, School of Medicine, and the Division of Medicinal Chemistry and Chemical Biology, Eshelman School of Pharmacy, and the NIMH Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Gavin AC; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA., Shah SD; Department of Medicine, Center for Translational Medicine and Division of Pulmonary, Allergy and Critical Care Medicine; Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA., Nayak AP; Department of Medicine, Center for Translational Medicine and Division of Pulmonary, Allergy and Critical Care Medicine; Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA., Haugaard-Kedström LM; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark., Penn RB; Department of Medicine, Center for Translational Medicine and Division of Pulmonary, Allergy and Critical Care Medicine; Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA., Roth BL; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Pharmacology, School of Medicine, and the Division of Medicinal Chemistry and Chemical Biology, Eshelman School of Pharmacy, and the NIMH Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Bräuner-Osborne H; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: hbo@sund.ku.dk., Gloriam DE; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: david.gloriam@sund.ku.dk.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2019 Oct 31; Vol. 179 (4), pp. 895-908.e21.
DOI:	10.1016/j.cell.2019.10.010
Abstrakt:	The peptidergic system is the most abundant network of ligand-receptor-mediated signaling in humans. However, the physiological roles remain elusive for numerous peptides and more than 100 G protein-coupled receptors (GPCRs). Here we report the pairing of cognate peptides and receptors. Integrating comparative genomics across 313 species and bioinformatics on all protein sequences and structures of human class A GPCRs, we identify universal characteristics that uncover additional potential peptidergic signaling systems. Using three orthogonal biochemical assays, we pair 17 proposed endogenous ligands with five orphan GPCRs that are associated with diseases, including genetic, neoplastic, nervous and reproductive system disorders. We also identify additional peptides for nine receptors with recognized ligands and pathophysiological roles. This integrated computational and multifaceted experimental approach expands the peptide-GPCR network and opens the way for studies to elucidate the roles of these signaling systems in human physiology and disease. VIDEO ABSTRACT. (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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