Omotuyi I. Olaposi*, Nash Oyekanmi, Metibemu D. Samuel, Ojochenemi A. Enejoh, Ukwenya O. Victor and Adelakun Niyi Pages 212 - 222 ( 11 )
Background: Takeda G-protein receptor 5 (TGR5) via glucagon-like peptide release and insulin signaling underlies antidiabetic roles of TGR5 agonists. Chromolaena Odorata- derived flavonoid-5,7-dihydroxy-6-4-dimethoxyflavanone (COF) has been identified as (TGR5) agonist. The structural basis for their interaction has not been studied.
Objective: This study aimed at providing both structural and dynamic insights into COF/TGR5 interaction.
Methods: Classical GPCR activation signatures (TMIII-TMVI ionic lock, toggle switches, internal water pathway) using classical MD simulation have been used.
Results: Y893.29, N933.33 and E1695.43 are key residues found to be involved in ligand binding; the continuous internal water pathway connects hydrophilic groups of the ligand to the TMIII-TMVI interface in COF-bound state, TMIII-TMVI ionic locks ruptures in COF-TGR5 complex but not antagonist-bound state, and ruptured ionic lock is associated with the evolution of active-state “VPVAM” (analogous to “NPxxY”) conformation. Dihedral angles (c2) calculated along the trajectory strongly suggest W2376.48 as a ligand-dependent toggle switch.
Conclusion: TGR5 evolves active state conformation from a starting intermediate state conformation when bound to COF, which further supports its underlying anti-diabetic activities.
TGR5, Chromolaena odorata-derived flavonoid, internal water pathway, ionic lock, homology- based modeling, molecular dynamic simulation.
Center for Bio-Computing and Drug Development, Adekunle Ajasin University, Akungba-Akoko, Ondo State, National Biotechnology Development Agency, Abuja, Center for Bio-Computing and Drug Development, Adekunle Ajasin University, Akungba-Akoko, Ondo State, National Biotechnology Development Agency, Abuja, Department of Human Anatomy, School of Health and Health Technology, Federal University of Science and Technology, Akure, Ondo State, Center for Bio-Computing and Drug Development, Adekunle Ajasin University, Akungba-Akoko, Ondo State