Abstract
Tyramine receptor (TyrR) is a biogenic amine G protein-coupled receptor (GPCR) associated with many important physiological functions in insect locomotion, reproduction, and pheromone response. Binding of specific ligands to the TyrR triggers conformational changes, relays the signal to G proteins, and initiates an appropriate cellular response. Here, we monitor the binding effect of agonist compounds, tyramine and amitraz, to a Sitophilus oryzae tyramine receptor (SoTyrR) homology model and their elicited conformational changes. All-atom molecular dynamics (MD) simulations of SoTyrR-ligand complexes have shown varying dynamic behavior, especially at the intracellular loop 3 (IL3) region. Moreover, in contrast to SoTyrR-tyramine, SoTyrR-amitraz and non-liganded SoTyrR shows greater flexibility at IL3 residues and were found to be coupled to the most dominant motion in the receptor. Our results suggest that the conformational changes induced by amitraz are different from the natural ligand tyramine, albeit being both agonists of SoTyrR. This is the first attempt to understand the biophysical implication of amitraz and tyramine binding to the intracellular domains of TyrR. Our data may provide insights into the early effects of ligand binding to the activation process of SoTyrR.
Highlights
Octopamine (OA) and tyramine (TA) are tyrosine-derived biogenic amines that are vital to many physiological processes in insects
The binding site of octopamine and tyramine receptors is said to comprise of the following signature amino acids: (a) a negatively charged Asp in TM3 that interacts with the protonated amine group of the ligand[12,13,14]; (b) a closely spaced Ser in TM5 that interacts with the phenolic hydroxyl group of the ligand[14,15,16]; and (c) an aromatic cluster in TM6 that exhibits π − π or hydrophobic interactions with the aromatic group of the ligand[17,18]
Various G protein-coupled receptor (GPCR) crystal structures with 23 to 32% sequence identity were used as template
Summary
Octopamine (OA) and tyramine (TA) are tyrosine-derived biogenic amines that are vital to many physiological processes in insects. Specific for OctR, a Tyr residue in TM6 interacts with the β-hydroxyl group of OA The identity of these contact sites seems to indicate that the role of the biogenic amine is to trigger communication between TM3, TM5, and TM619,20. Several studies have used MD simulations in distinguishing the effects of different ligands to the activation of other related GPCRs, e.g. serotonin and adenosine receptor[24,25,26,27] These parallel studies have proven the importance of computational studies in explaining the ligand-dependent mechanism of various GPCRs. Experimental studies have been conducted on TyrR of other insects including silkworm (Bombyx mori), honeybee (Apis mellifera), cockroach (Periplaneta americana), cattle tick (Rhipicephalus microplus), and fruit fly (Drosophila melanogaster)[13,14,28,29,30,31]. We surmised that the importance of correlated motions within the receptor and the interplay of the amino acid residues in TMs and IL3 domain influences the activation process of SoTyrR in agreement with the general mechanism of GPCR activation
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