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

doi:10.3390/molecules24152752

Maicol Bissaro, Mattia Sturlese + Show 3 more

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https://doi.org/10.3390/molecules24152752

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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.

Highlights

The human genome encodes more than 800 different G protein-coupled receptors (GPCRs), membrane proteins characterized by a distinctive seven transmembrane helices (7TM)architecture
supervised molecular dynamics (SuMD) simulations allow for the simulation of intermolecular recognition pathways in a very compressed time scale
Considering the lack of reliable structural information on the unbound state of the receptor, the experimentally-determined inactive and intermediate active conformations of A2A Adenosine receptors (ARs) were retrieved from the Protein Data Bank (PDB) database

Summary

Introduction

This superfamily of receptors recognizes an enormous variety of extracellular signals (i.e., ions, neurotransmitters, peptides) and transmits the chemical information into the intracellular compartment, modulating many cellular activities [1,2,3]. This is achieved through the recruitment of different molecular effectors, such as G proteins, protein kinases, or β-arrestins. Adenosine receptors (ARs) are a family of class A GPCRs comprising four different subtypes, respectively, A1 , A2A , A2B , and A3 , all involved in purinergic signaling [3]. 46 structures deposited in the Molecules 2019, 24, 2752; doi:10.3390/molecules24152752 www.mdpi.com/journal/molecules

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