Revisiting the Allosteric Regulation of Sodium Cation on the Binding of Adenosine at the Human A2A Adenosine Receptor: Insights from Supervised Molecular Dynamics (SuMD) Simulations

Maicol Bissaro, Giovanni Bolcato, Giuseppe Deganutti, Mattia Sturlese, Stefano Moro

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Abstract

One of the most intriguing findings highlighted from G protein-coupled receptor (GPCR) crystallography is the presence, in many members of class A, of a partially hydrated sodium ion in the middle of the seven transmembrane helices (7TM) bundle. In particular, the human adenosine A2A receptor (A2A AR) is the first GPCR in which a monovalent sodium ion was crystallized in a distal site from the canonical orthosteric one, corroborating, from a structural point of view, its role as a negative allosteric modulator. However, the molecular mechanism by which the sodium ion influences the recognition of the A2A AR agonists is not yet fully understood. In this study, the supervised molecular dynamics (SuMD) technique was exploited to analyse the sodium ion recognition mechanism and how its presence influences the binding of the endogenous agonist adenosine. Due to a higher degree of flexibility of the receptor extracellular (EC) vestibule, we propose the sodium-bound A2A AR as less efficient in stabilizing the adenosine during the different steps of binding.
Original languageEnglish
Article number2752
Number of pages15
JournalMolecules
Volume24
Issue number15
DOIs
Publication statusPublished - 29 Jul 2019
Externally publishedYes

Bibliographical note

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Keywords

  • Adenosine Receptor
  • Agonist
  • Sodium Ion
  • Allosteric Modulator
  • Molecular Dynamics
  • Supervised Molecular Dynamics

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