A Comparison in the Use of the Crystallographic Structure of the Human A1 or the A2A Adenosine Receptors as a Template for the Construction of a Homology Model of the A3 Subtype

Enrico Margiotta,Stefano Moro

doi:10.3390/app9050821

Abstract

In the last decades, the field of therapeutic application in targeting the human A3 adenosine receptor has represented a rapidly growing area of research in adenosine field. Both agonists and antagonists have been described to have a potential application in the treatment of several diseases, including, for example, glaucoma, cancer, and autoimmune inflammations. To date, the most severe factor limiting the accuracy of the structure-based molecular modeling approaches is the fact that the three-dimensional human A3 structure has not yet been solved. However, the crystallographic structures of either human A1 or A2A subtypes are available as potential templates for the construction of its homology model. In this study, we have compared the propensity of both models to accommodate a series of known potent and selective human A3 agonists and antagonists. As described, on the basis of the results obtained from this preliminary study, it is possible to affirm that the human A3 receptor model based on the crystallographic structure of the A1 subtype can represent a valid alternative to the one conventionally used today, based on the available A2A structures.

Highlights

Adenosine is a key extracellular signaling molecule that regulates the cellular responses to tissue damage, hypoxia, and energy depletion, through activation of G protein-coupled receptors [1]
The simplest template selection rule is to select the structure with the highest sequence similarity to the modeled sequence [57]
These results indicate that, ideally, the orthosteric site of the hA3 adenosine receptor (AR) active state may the peculiar substituents of selective agonists in the proximity of EL2 and TMs 2-3 through some accommodate the peculiar substituents of selective agonists in the proximity of EL2 and TMs 2-3 expansion of the cavity, favored by the conserved and not conserved residues located in these regions, through some expansion of the cavity, favored by the conserved and not conserved residues located as Leu90 (3.32) [58], Gln167 (EL2) [59] and Thr94 (3.36)

Summary

Introduction

Adenosine is a key extracellular signaling molecule that regulates the cellular responses to tissue damage, hypoxia, and energy depletion, through activation of G protein-coupled receptors [1]. The human A3 AR subtype (hA3 AR) was the last member of the adenosine family to have been cloned It was originally described in 1991 by Meyerhof and collaborators as an orphan receptor from rat testis and coded as tgpcr, sharing 40% of sequence similarity with canine A1 and A2A ARs [2]. Zhou and collaborators described the cDNA sequence, initially named R226 and extracted from the rat striatum, that encoded for a G protein-coupled receptor with an identical sequence of tgpcr and able to bind adenosine [3]. This experimental evidence led to the conclusion that it was a new AR subtype, namely A3.

Methods

Results

Conclusion