Biochemistry & Molecular Biology Journal Open Access

Takeda G-protein receptor (TGR)-5 evolves classical activestate conformational signatures in complex with Chromolaena Odorata flavonoid

EuroSciCon conference on Protein, Proteomics and Computational Biology

December 06-07, 2018 Amsterdam, Netherlands

Omotuyi Idowu Olaposi and Nash Oyekanmi

Center for Bio-Computing and Drug Development-Adekunle Ajasin University (Nigeria) Center for Genomics Research and Innovation-National Biotechnology Development Agency (Nigeria))

Posters & Accepted Abstracts: Biochem Mol biol J

Abstract:

Chromolaena Odorata-derived flavonoid-5, 7-dihydroxy-6-4-dimethoxyflavanone (COF) has been identified as a major antidiabetic agent targeting Takeda G-protein receptor 5 (TGR5) activation resulting in glucagon-like peptide-1 stimulation. This study provides structural and dynamic insights into COF/TGR5 interaction by investigating classical GPCR activation signatures (TMIII-TMVI ionic lock, toggle switches, internal water pathway) in comparison with known agonist (INT-777), antagonist (triamterene, TRX) and apo-state using MD simulation. Y893.29, N933.33 and S2707.42 are key residues involved in ligand binding. Continuous internal water pathway connects the hydrophilic substituents of the ligand to the TMIII-TMVI interface in COF and INT-777 bound TGR5 but not TRX-bound TGR5. TMIII-TMVI ionic locks are ruptured in COF and INT-777 bound TGR5 but not TRXbound, ionic lock rupture is associated with evolution of active-state “VPVAM” (analogous to NPxxY) conformation. Dihedral angles (χ2) calculated along the trajectory strongly suggest W2376.48 as a ligand-dependent but not agonist-dependent toggle switch. In conclusion, TGR5 evolves active state conformation from a starting intermediate state conformation when bound to COF and INT-777, which further explains their underlying anti-diabetic activities.

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