Molecular Recognition of Agonists and Antagonists by the Nucleotide-Activated G Protein-Coupled P2Y2 Receptor

Muhammad Rafehi, Alexander Neumann, Younis Baqi, Enas M. Malik, Michael Wiese, Vigneshwaran Namasivayam, Christa E. Müller

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

A homology model of the nucleotide-activated P2Y2R was created based on the X-ray structures of the P2Y1 receptor. Docking studies were performed, and receptor mutants were created to probe the identified binding interactions. Mutation of residues predicted to interact with the ribose (Arg110) and the phosphates of the nucleotide agonists (Arg265, Arg292) or that contribute indirectly to binding (Tyr288) abolished activity. The Y114F, R194A, and F261A mutations led to inactivity of diadenosine tetraphosphate and to a reduced response of UTP. Significant reduction in agonist potency was observed for all other receptor mutants (Phe111, His184, Ser193, Phe261, Tyr268, Tyr269) predicted to be involved in agonist recognition. An ionic lock between Asp185 and Arg292 that is probably involved in receptor activation interacts with the phosphate groups. The antagonist AR-C118925 and anthraquinones likely bind to the orthosteric site. The updated homology models will be useful for virtual screening and drug design.

Original languageEnglish
Pages (from-to)8425-8440
Number of pages16
JournalJournal of Medicinal Chemistry
Volume60
Issue number20
DOIs
Publication statusPublished - Oct 26 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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