Abstract
α2-adrenergic receptors play a key role in the regulation of sympathetic system, neurotransmitter release, blood pressure and intraocular pressure. Although α2-adrenergic receptors mediate a number of physiological functions in vivo and have great therapeutic potential, the absence of crystal structure of α2-adrenergic receptor subtypes is a major hindrance in the drug design efforts. The therapeutic efficacy of the available drugs is not selective for subtype specificity (α2a, α2b and α2c) leading to unwanted side effects. We used Homology modelling and docking studies to understand and analyze the residues important for agonist and antagonist binding. We have also analyzed binding site volume, and the residue variations which may play important role in ligand binding. We have identified residues through our modelling and docking studies, which would be critical in giving subtype specificity and may help in the development of future subtype-selective drugs.
Highlights
Alpha2-adrenergic receptors (α2-ARs) belong to adrenergic receptor family
This was followed by the availability of other members of GPCR family, Human β2-adrenergic receptor [26], turkey β1-adrenergic receptor [27], squid Rhodopsin [28], Human adenosine A2a receptor [29], chemokine CXCR4 [30], Human Dopamine D3 receptor in complex with a D2/ D3 selective antagonist Eticlopride [31], and most recently histamine H1 (H1R) [32], M3 muscarinic acetylcholine receptor [33], Mu-opioid receptor [34], a lipid G protein-coupled receptor [35], M2 muscarinic receptor [36], Kappa opioid [37], Delta opioid [38], Neurotensin receptor 1 [39], chemokine CXCR1 [40], Protease activated receptor 1 [41], 5-hydroxytryptamine 1b [42], and 5-hydroxytryptamine 2b
As the available models of α2a, α2b- and α2c- ARs was based on either rhodopsin or β-adrenergic receptor, we suggest that the model based on Dopamine may prove better than rhodopsin/ beta adrenergic based model in predicting residues important for subtype specificity, as it shares more sequence identity in the transmembrane region compared to available GPCRs
Summary
Alpha2-adrenergic receptors (α2-ARs) belong to adrenergic receptor family. There are nine representative members is adrenergic family namely, α1a, α1b, α1d, α2a, α2b, α2c, β1, β2, and β3. Homology modelling and docking studies were earlier based on bovine Rhodopsin even though it showed lower sequence identity (21%) and lower transmembrane identity (26%) as the availability of high resolution GPCR structures was the limitation [18,19,20,21,22,23,24,25] This was followed by the availability of other members of GPCR family, Human β2-adrenergic receptor [26], turkey β1-adrenergic receptor [27], squid Rhodopsin [28], Human adenosine A2a receptor [29], chemokine CXCR4 [30], Human Dopamine D3 receptor in complex with a D2/ D3 selective antagonist Eticlopride [31], and most recently histamine H1 (H1R) [32], M3 muscarinic acetylcholine receptor [33], Mu-opioid receptor [34], a lipid G protein-coupled receptor [35], M2 muscarinic receptor [36], Kappa opioid [37], Delta opioid [38], Neurotensin receptor 1 [39], chemokine CXCR1 [40], Protease activated receptor 1 [41], 5-hydroxytryptamine 1b [42], and 5-hydroxytryptamine 2b
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