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Impact of Intracellular Proteins on μ-Opioid Receptor Structure and Ligand Binding. | LitMetric

AI Article Synopsis

  • * The signaling pathways of MOR involve two main routes: the G pathway, which manages pain relief, and the β-arrestin pathway, linked to adverse effects; the goal is to develop painkillers that only trigger the beneficial G pathway.
  • * Research through structural analysis and quantum calculations suggests that different conformations of fentanyl can bind to MOR, potentially leading to varied intracellular signaling and effects, highlighting the complexity of opioid interactions with the receptor.

Article Abstract

Chronic pain is a prevalent problem affecting approximately one out of every five adults in the U.S. The most effective way to treat chronic pain is with opioids, but they cause dangerous side effects such as tolerance, addiction, and respiratory depression, which makes them quite deadly. Opioids, such as fentanyl, target the μ-opioid receptor (MOR), which can then bind to the intracellular G protein or the β-arrestin protein. The G pathway is primarily responsible for pain relief and potential side effects, but the β-arrestin pathway is chiefly responsible for the unwanted side effects. Ideally, an effective pain medication without side effects would bind to MOR, which would bias signaling solely through the G pathway. We used the Bio3D library to conduct principal component analysis to compare the cryo-electron microscopy MOR structures in complex with the G versus an X-ray crystallography MOR structure with a nanobody acting as a G mimic. Our results agree with a previous study by Munro, which concluded that nanobody-bound MOR is structurally different than G-bound MOR. Furthermore, we investigated the structural diversity of opioids that can bind to MOR. Quantum mechanical calculations show that the low energy solution structures of fentanyl differ from the one bound to MOR in the experimental structure, and p calculations reveal that fentanyl is protonated in aqueous solution. Glide docking studies show that higher energy structures of fentanyl in solution form favorable docking complexes with MOR. Our calculations show the relative abundance of each fentanyl conformation in solution as well as the energetic barriers that need to be overcome to bind to MOR. Docking studies confirm that multiple fentanyl conformations can bind to the receptor. Perhaps a variety of conformations of fentanyl can stabilize multiple conformations of the MOR, which can explain why fentanyl can induce different intracellular signaling and multiple physiological effects.

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Source
http://dx.doi.org/10.1021/acs.jpcb.4c05214DOI Listing

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