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Volume 10, Issue 8 (Suppl)
J Proteomics Bioinform, an open access journal
ISSN: 0974-276X
Structural Biology 2017
September 18-20, 2017
9
th
International Conference on
Structural Biology
September 18-20, 2017 Zurich, Switzerland
Arfaxad Reyes Alcaraz, J Proteomics Bioinform 2017, 10:8(Suppl)
DOI: 10.4172/0974-276X-C1-0100
Structural conformational changes report biased agonism: The case of galanin receptors
Arfaxad Reyes Alcaraz
Korea University, South Korea
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 aimof 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.
Biography
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.
aramarfa47@gmail.comFigure: A) Five NLuc-ß-arrestin 2-FIASH BRET structural biosensors (F1-F5) were
constructed by inserting the amino acid motif CCPGCC after amino acid residues 40,
140, 171 263 and 410 of ß-arrestin2. The location of each FIASH motif is shown in
relation to the globular N and C domains of ß-arrestin2. B) Diagram of the structural
complementation assay used to measure in real time binding between ß-arrestin2
and Galanin receptors. C) Schematic diagram depicting levels of conformational
aberration produced in different areas of the receptor upon stabilization of receptor
conformations by different agonists. Arrows depict various regions of interaction of the
receptor with cytosolic proteins such as different G-proteins and ß-arrestin. It might
be surmised that dissimilar conformations affect these various regions to varying
degrees causing respective differences in effect for diverse coupling mechanisms.