Probing biased activation of mu-opioid receptor by the biased agonist PZM21 using all atom molecular dynamics simulation

Morphine is a commonly used opioid drug to treat acute pain by binding to the mu-opioid receptor (MOR), but its effective analgesic efficacy via triggering of the heterotrimeric Gi protein pathway is accompanied by a series of adverse side effects via triggering of the beta-arrestin pathway. Recently, PZM21, a recently developed MOR biased agonist, shows preferentially activating the G protein pathway over beta-arrestin pathway. However, there is no high-resolution receptor structure in complex with PZM21 and its action mechanism remains elusive. In this study, PZM21 and Morphine were docked to the active human MOR-1 homology structure and then subjected to the molecular dynamics (MD) simulations in two different situations (i.e., one situation includes the crystal waters but another does not). Detailed comparisons between the two systems were made to characterize the differences in protein-ligand interactions, protein secondary and tertiary structures and dynamics networks. PZM21 could strongly interact with Y328(7.43) of TM7, besides the residues (Asp149(3.32) and Tyr150(3.33)) of TM3. The two systems' network paths to the intracellular end of TM6 were roughly similar but the paths to the end of TM7 were different. The PZM21-bound MOR's intracellular ends of TM5-7 bent outward more along with the distance changes of the three key molecular switches (ionic lock, transmission and Tyr toggle) and the distance increase of some conserved inter-helical residue pairs. The larger intracellular opening of the receptor could potentially facilitate G protein binding.

Automated summary

This study compared the binding and action mechanisms of the MOR biased agonist PZM21 and morphine to the mu-opioid receptor, revealing that PZM21 preferentially activates the G protein pathway over the beta-arrestin pathway. The interaction between PZM21 and MOR led to conformational changes and altered amino acid interactions within the receptor, potentially facilitating G protein binding.