Title: Elucidation of Protein Motion, Allostery, and Intra-Molecular Signaling of GPCR, and Its Application to Rational Drug Discovery


Speaker: Sun Choi, Ph.D., College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University (Host : Iksoo Chang)


Time: 16:00, September 5 (Wed), 2018
        

Venue: Room 114, Building E4, DGIST


Abstract : G protein-coupled receptors (GPCRs) act as both gatekeeper and molecular messengers of the cell converting extracellular signals to cellular activities. Hence, elucidation of its allosteric modulation and related intra-molecular signaling would be of great help. To investigate the allosteric regulation of GPCR, we adopted network centrality analysis to the apo and agonist-bound forms of A2A adenosine receptor (A2AAR). Through the analysis, we could precisely identify the location of micro-switches which are deemed critical for GPCR activation. Additionally, significant long-range communications were found to exist between the extracellular ligand binding site and G protein binding site in the agonist-bound form only.
Recently, we discovered novel modulators of A3AR and identified minute chemical changes crossover the boundary between agonistic and antagonistic effects. To investigate this effect, new A3AR homology models were constructed based on pharmacological profiles of the ligands. To account for the protein flexibility, the binding modes were predicted using multiple receptor conformations (MRCs). The results showed that the H-bonding with T94 is crucial for the agonistic effect of A3AR. Interestingly, the network analysis also confirmed that T94 is important for signal flow in the receptor. Taken together, our structure-based studies using MRCs and network analysis can provide valuable insights into the allosteric modulation of GPCRs, and they could be utilized as a powerful tool in drug discovery.


Person in charge : Sora Lee


Contact: srlee@dgist.ac.kr, 053)785-6102