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|Arfaxad Reyes Alcaraz|
|Korea University, South Korea|
|ScientificTracks Abstracts: J Proteomics Bioinform|
|Statement of the Problem: G protein coupled receptors (GPCRs), also known as seven-transmembrane receptors are the largest family of cell-surface receptors that communicate extracellular stimuli to the cell interior. To date it has been widely accepted synthetic ligands targeting the same receptor can stabilize multiple active structural conformations having therefore differential signaling that eventually results in different physiological responses a phenomenon better known as biased agonism. However biased agonism might not only be restricted to synthetic ligands but also to endogenous ligands targeting the same receptor which may explain such a ligand redundancy, suggesting the existence of endogenous biased agonism as a physiological mechanism. Methodology & Theoretical Orientation: The aim of this study was to establish a relationship between conformational changes in galanin receptors and their signaling properties in living cells. For that purpose, we developed a structural complementation assay based on NanoBit technology and a series of conformational fluorescein arsenical hairpin (FIAsH) bioluminescence resonance energy transfer (BRET) biosensors to monitor structural changes of β-arrestin 2 induced by binding with each galanin receptor. Findings: Here we showed that galanin receptors impose different conformational signatures in β-arrestin, moreover structurally different ligands activating the same receptor imposed different conformations in β-arrestin 2 producing biased signaling. Conclusion & Significance: Our data provide definite evidence that a receptor activated by structurally different ligands can adopt multiple active conformations. Moreover, this finding also demonstrates that functionally specific structural galanin receptor conformations can indeed be translated to downstream effectors producing a different physiological response.|
Arfaxad Reyes Alcaraz has his expertise in structure and stability of G-protein coupled receptors and passion for improving and creating new drug discovery platforms that greatly contribute in the development of more selective drugs with minor side effects. His studies about biased agonism in galanin receptors helped to understand the relationship between conformational structure of the receptor and its corresponding physiological effect induced by a specific ligand. Recently, he and his co-workers were able to develop a highly selective agonist for galanin receptor 2 with anxiolytic effect in vivo which was the base to discover how different ligand structures induce different conformations on the structure of galanin receptors. His works greatly contribute to understand the relationship between structure and function of galanin receptors.
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