2018
DOI: 10.1016/j.tips.2017.11.001
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Structural Mapping of Adenosine Receptor Mutations: Ligand Binding and Signaling Mechanisms

Abstract: The four adenosine receptors (ARs), A, A, A, and A, constitute a subfamily of G protein-coupled receptors (GPCRs) with exceptional foundations for structure-based ligand design. The vast amount of mutagenesis data, accumulated in the literature since the 1990s, has been recently supplemented with structural information, currently consisting of several inactive and active structures of the A and inactive conformations of the A ARs. We provide the first integrated view of the pharmacological, biochemical, and st… Show more

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Cited by 72 publications
(87 citation statements)
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References 78 publications
(126 reference statements)
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“…As a general view, the incoming adenosine molecule competed with the orthosteric one by interacting with key amino acids that are fundamental for the adenosine binding . This aspect may complicate the experimental confirmation of our findings by means of mutagenesis experiments, as a modification of residues implicated in the orthosteric interaction pattern should abolish also the formation of the orthosteric complex with stoichiometry 1 : 1.…”
Section: Discussionmentioning
confidence: 82%
“…As a general view, the incoming adenosine molecule competed with the orthosteric one by interacting with key amino acids that are fundamental for the adenosine binding . This aspect may complicate the experimental confirmation of our findings by means of mutagenesis experiments, as a modification of residues implicated in the orthosteric interaction pattern should abolish also the formation of the orthosteric complex with stoichiometry 1 : 1.…”
Section: Discussionmentioning
confidence: 82%
“…On the one hand, it binds endogenous adenosine, which regulates vasodilation, inflammation [55] and affects the central nervous system (CNS), inhibiting dopaminergic activity [56]. On the other hand, the inhibition of A2aR by molecules like caffeine leads to an increase in dopaminergic activity, which makes antagonists of A2aR an important target for treating Parkinson's [57] and Alzheimer's diseases [58,59]. Despite current knowledge, to date, only one selective A2aR agonist (Regadenoson) has gained FDA approval, as well as an antagonist (Istradefylline), which in combination with levodopa is used for the treatment of Parkinson's disease in Japan [58,59].…”
Section: Introductionmentioning
confidence: 99%
“…Approximate binding modes are therefore often inferred from the experimental data extracted from (SAR) of ligand series and SDM data. 21 Both of these methods are however most powerful when complemented by computational models of the protein-ligand complex. 23 One such a method, coined Biophysical Mapping (BPM), is an integrated approach that has been used with success in antagonist design programs on the A2AAR and other GPCRs.…”
Section: N Introductionmentioning
confidence: 99%
“…Here, reasonable binding modes were generated by molecular docking, resulting in two binding modes of chromone 14 (see Figure 1), each forming at least one hydrogen bond with Asn253 6.55 (a highly conserved interaction in AR ligand recognition). 21 The two poses, denoted as A and B in Figure 2, are related by a symmetry axis along the bicyclic core of the chromone scaffold, and were energetically equivalent according to the docking score function used (-9.30 vs -9.17 for pose A and B respectively). These docking results are in line with the previous hypothesis from Andrews et al, 27,29 In pose A (Figure 2A), Asn253 6.55 forms a H-bond with the nitrogen in the 4-methyltiazole group, leaving the carbonyl group potentially exposed to the internal water network stabilized by residues in TM7, as observed in the A2AAR crystal structure with ZM241385.…”
Section: N Introductionmentioning
confidence: 99%
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