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Ligand binding and activation of UTP-activated G protein-coupled P2Y2 and P2Y4 receptors elucidated by mutagenesis, pharmacological and computational studies.

Authors
  • Attah, Isaac Y1
  • Neumann, Alexander2
  • Al-Hroub, Haneen1
  • Rafehi, Muhammad1
  • Baqi, Younis2
  • Namasivayam, Vigneshwaran1
  • Müller, Christa E3
  • 1 PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Sciences Bonn (PSB), Pharmaceutical & Medicinal Chemistry, University of Bonn, Germany. , (Germany)
  • 2 PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Sciences Bonn (PSB), Pharmaceutical & Medicinal Chemistry, University of Bonn, Germany; Department of Chemistry, Faculty of Science, Sultan Qaboos University, PO Box 36, Postal Code 123 Muscat, Oman. , (Germany)
  • 3 PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Sciences Bonn (PSB), Pharmaceutical & Medicinal Chemistry, University of Bonn, Germany. Electronic address: [email protected] , (Germany)
Type
Published Article
Journal
Biochimica et biophysica acta. General subjects
Publication Date
Dec 05, 2019
Volume
1864
Issue
3
Pages
129501–129501
Identifiers
DOI: 10.1016/j.bbagen.2019.129501
PMID: 31812541
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The nucleotide receptors P2Y2 and P2Y4 are the most closely related G protein-coupled receptors (GPCRs) of the P2Y receptor (P2YR) family. Both subtypes couple to Gq proteins and are activated by the pyrimidine nucleotide UTP, but only P2Y2R is also activated by the purine nucleotide ATP. Agonists and antagonists of both receptor subtypes have potential as drugs e.g. for neurodegenerative and inflammatory diseases. So far, potent and selective, "drug-like" ligands for both receptors are scarce, but would be required for target validation and as lead structures for drug development. Structural information on the receptors is lacking since no X-ray structures or cryo-electron microscopy images are available. Thus, we performed receptor homology modeling and docking studies combined with mutagenesis experiments on both receptors to address the question how ligand binding selectivity for these closely related P2YR subtypes can be achieved. The orthosteric binding site of P2Y2R appeared to be more spacious than that of P2Y4R. Mutation of Y197 to alanine in P2Y4R resulted in a gain of ATP sensitivity. Anthraquinone-derived antagonists are likely to bind to the orthosteric or an allosteric site depending on their substitution pattern and the nature of the orthosteric binding site of the respective P2YR subtype. These insights into the architecture of P2Y2- and P2Y4Rs and their interactions with structurally diverse agonists and antagonist provide a solid basis for the future design of potent and selective ligands. Copyright © 2019 Elsevier B.V. All rights reserved.

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