Structure Insights into Biased Signaling of kappa Opioid Receptor

Abstract

κ‐opioid receptor (KOR) has been known as an attractive drug target for pain management because it offers anti‐nociception without causing constipation, euphoria, or respiratory depression that accompany traditional analgesics targeting the μ‐opioid receptor (MOR). Although negative side‐effects of KOR activation prevent the adoption of most KOR‐based analgesics such as hallucinations, dysphoria, and sedation, nalfurafine is the only clinically available KOR agonist that shows atypical properties relative to other KOR agonists such as no hallucination and no dysphoria. To better understand the molecular determinants that drive KOR’s therapeutic property, here we reported the crystal structure of KOR bound to nalfurafine and identified the structural features that contribute to nalfurafine’s high potency and unique signaling profile. Using atomic‐level molecular dynamics (MD) simulations of KOR bound to G protein‐biased nalfurafine and other differently biased ligands, we identified receptor conformations that cause nalfurafine’s favorable therapeutic profile and provide a hypothesis for the structural basis for signaling bias at KOR in general.