Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity.

ABSTRACT: While the therapeutic effect of opioids analgesics is mainly attributed to µ-opioid receptor (MOR) activation leading to G protein signaling, their side effects have mostly been linked to β-arrestin signaling. To shed light on the dynamic and kinetic elements underlying MOR functional selectivity, we carried out close to half millisecond high-throughput molecular dynamics simulations of MOR bound to a classical opioid drug (morphine) or a potent G protein-biased agonist (TRV-130). Statistical analyses of Markov state models built using this large simulation dataset combined with information theory enabled, for the first time: a) Identification of four distinct metastable regions along the activation pathway, b) Kinetic evidence of a different dynamic behavior of the receptor bound to a cla

SUBMITTER: Kapoor A 

PROVIDER: S-EPMC5595830 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature