Structural basis for μ-opioid receptor binding and activation

Adrian W.R. Serohijos, Shuangye Yin, Feng Ding, Josee Gauthier, Dustin G. Gibson, William Maixner, Nikolay Dokholyan, Luda Diatchenko

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Opioids that stimulate the μ-opioid receptor (MOR1) are the most frequently prescribed and effective analgesics. Here we present a structural model of MOR1. Molecular dynamics simulations show a ligand-dependent increase in the conformational flexibility of the third intracellular loop that couples with the G protein complex. These simulations likewise identified residues that form frequent contacts with ligands. We validated the binding residues using site-directed mutagenesis coupled with radioligand binding and functional assays. The model was used to blindly screen a library of ∼1.2 million compounds. From the 34 compounds predicted to be strong binders, the top three candidates were examined using biochemical assays. One compound showed high efficacy and potency. Post hoc testing revealed this compound to be nalmefene, a potent clinically used antagonist, thus further validating the model. In summary, the MOR1 model provides a tool for elucidating the structural mechanism of ligand-initiated cell signaling and for screening novel analgesics.

Original languageEnglish (US)
Pages (from-to)1683-1690
Number of pages8
JournalStructure
Volume19
Issue number11
DOIs
StatePublished - Nov 9 2011

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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