Conserved residues in RF-NH2 receptor models identify predicted contact sites in ligand–receptor binding
2014
Bass, C. | Katanski, C. | Maynard, B. | Zurro, I. | Mariane, E. | Matta, M. | Loi, M. | Melis, V. | Capponi, V. | Muroni, P. | Setzu, M. | Nichols, R.
Peptides in the RF-NH2 family are grouped together based on an amidated dipeptide C terminus and signal through G-protein coupled receptors (GPCRs) to influence diverse physiological functions. By determining the mechanisms underlying RF-NH2 signaling targets can be identified to modulate physiological activity; yet, how RF-NH2 peptides interact with GPCRs is relatively unexplored. We predicted conserved residues played a role in Drosophila melanogaster RF-NH2 ligand–receptor interactions. In this study D. melanogaster rhodopsin-like family A peptide GPCRs alignments identified eight conserved residues unique to RF-NH2 receptors. Three of these residues were in extra-cellular loops of modeled RF-NH2 receptors and four in transmembrane helices oriented into a ligand binding pocket to allow contact with a peptide. The eighth residue was unavailable for interaction; yet its conservation suggested it played another role. A novel hydrophobic region representative of RF-NH2 receptors was also discovered. The presence of rhodopsin-like family A GPCR structural motifs including a toggle switch indicated RF-NH2s signal classically; however, some features of the DMS receptors were distinct from other RF-NH2 GPCRs. Additionally, differences in RF-NH2 receptor structures which bind the same peptide explained ligand specificity. Our novel results predicted conserved residues as RF-NH2 ligand–receptor contact sites and identified unique and classic structural features. These discoveries will aid antagonist design to modulate RF-NH2 signaling.
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