Could Adenosine Recognize its Receptors with a Stoichiometry Other than 1 : 1?

G Deganutti, V Salmaso, S Moro

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

One of the most largely accepted concepts in the G protein‐coupled receptors (GPCRs) field is that the ligand, either agonist or antagonist, recognizes its receptor with a stoichiometry of 1 : 1. Recent experimental evidence, reporting ternary complexes formed by GPCR:orthosteric: allosteric ligands, has complicated the ligand‐receptor 1 : 1 binding scenario. Molecular modeling simulations have been used to retrieve insights on the whole ligand‐receptor recognition process, beyond information on the final bound state provided by experimental techniques. The simulation of adenosine binding pathways towards the A2A adenosine receptor highlighted the presence of alternative binding sites (meta‐binding sites) beside the canonical orthosteric one, mainly in proximity to the extracellular vestibule. In light of all these considerations, we investigated the possibility that a second molecule of adenosine engages its receptor when this is already in the holo form, generating a ternary complex with a stoichiometry of 2 : 1. Unexpectedly, supervised molecular dynamics (SuMD) simulations showed that the A2A adenosine receptor could bind the second molecule of adenosine in one of the possible meta‐binding sites as well as into its orthosteric site. The formation of this ternary complex, which favored the formation of the intracellular “ionic lock” between R102 (3.50) and E228 (6.30), could putatively be framed in the context of a negative allosteric regulation.
Original languageEnglish
Article number1800009
JournalMolecular informatics
Volume37
Issue number8
Early online date19 Apr 2018
DOIs
Publication statusPublished - 8 Aug 2018
Externally publishedYes

Keywords

  • Adenosine
  • adenosine receptor
  • agonist stoichiometry
  • molecular dynamics
  • supervised molecular dynamics

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