Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor

Cell. 2018 Jan 11;172(1-2):55-67.e15. doi: 10.1016/j.cell.2017.12.011. Epub 2018 Jan 4.


The κ-opioid receptor (KOP) mediates the actions of opioids with hallucinogenic, dysphoric, and analgesic activities. The design of KOP analgesics devoid of hallucinatory and dysphoric effects has been hindered by an incomplete structural and mechanistic understanding of KOP agonist actions. Here, we provide a crystal structure of human KOP in complex with the potent epoxymorphinan opioid agonist MP1104 and an active-state-stabilizing nanobody. Comparisons between inactive- and active-state opioid receptor structures reveal substantial conformational changes in the binding pocket and intracellular and extracellular regions. Extensive structural analysis and experimental validation illuminate key residues that propagate larger-scale structural rearrangements and transducer binding that, collectively, elucidate the structural determinants of KOP pharmacology, function, and biased signaling. These molecular insights promise to accelerate the structure-guided design of safer and more effective κ-opioid receptor therapeutics.

Keywords: GPCR; active state; addiction; crystallography; morphinan; nanobody; opioid receptor; structure-function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Animals
  • Binding Sites
  • HEK293 Cells
  • Humans
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation
  • Morphinans / chemistry
  • Morphinans / pharmacology
  • Protein Binding
  • Protein Stability
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / chemistry*
  • Receptors, Opioid, kappa / metabolism
  • Sf9 Cells
  • Spodoptera


  • 17-cyclopropylmethyl-3-hydroxy-4,5-epoxy-7,8-en-6-((3'-iodo)benzamido)morphinan
  • Analgesics
  • Morphinans
  • Receptors, Opioid, kappa