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Biased Agonist TRV027 Determinants in AT1R by Molecular Dynamics Simulations.
Journal of Chemical Information and Modeling 2019 January 23
Functional selectivity is a phenomenon observed in G protein coupled-receptors (GPCR) in which intermediate active states conformations are stabilized by mutations or ligand binding, resulting in different sets of signaling pathways. Peptides capable of selectively activating β-arrestin, known as biased agonists, have already been characterized in vivo, and could correspond to a new therapeutic approach for cardiovascular diseases treatment. Despite biased agonism potential, the mechanism involved in selective signaling remains unclear. In this work, molecular dynamics simulations were employed to compare the conformational profile of AT1R crystal bond to angiotensin II (AngII), bond to the biased ligand TRV027 and in the apo form. Our results show that both ligands induce changes near the NPxxY motif in TM7 that are related to receptor activation. However, the biased ligand does not cause the rotamer toggle alternative positioning and displays an exclusive hydrogen bond pattern. Our work sheds light into biased agonism mechanism and will help future design of novel biased agonist for AT1R.
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