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
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
Conclusion: TGR5 evolves active state conformation from a starting intermediate state conformation
when bound to COF, which further supports its underlying anti-diabetic activities.