Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic

Nature. 2012 May 16;485(7398):395-9. doi: 10.1038/nature11085.

Abstract

Members of the opioid receptor family of G-protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system, where they have key roles in nociception and analgesia. Unlike the 'classical' opioid receptors, δ, κ and μ (δ-OR, κ-OR and μ-OR), which were delineated by pharmacological criteria in the 1970s and 1980s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, also known as ORL-1) was discovered relatively recently by molecular cloning and characterization of an orphan GPCR. Although it shares high sequence similarity with classical opioid GPCR subtypes (∼60%), NOP has a markedly distinct pharmacology, featuring activation by the endogenous peptide N/OFQ, and unique selectivity for exogenous ligands. Here we report the crystal structure of human NOP, solved in complex with the peptide mimetic antagonist compound-24 (C-24) (ref. 4), revealing atomic details of ligand-receptor recognition and selectivity. Compound-24 mimics the first four amino-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to the binding of these peptides. The X-ray structure also shows substantial conformational differences in the pocket regions between NOP and the classical opioid receptors κ (ref. 5) and μ (ref. 6), and these are probably due to a small number of residues that vary between these receptors. The NOP-compound-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands.

Publication types

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

MeSH terms

  • Binding Sites
  • Biomimetic Materials / chemistry*
  • Biomimetic Materials / metabolism
  • Biomimetic Materials / pharmacology
  • Crystallography, X-Ray
  • HEK293 Cells
  • Humans
  • Ligands
  • Models, Molecular
  • Narcotic Antagonists
  • Opioid Peptides / chemistry*
  • Opioid Peptides / metabolism
  • Opioid Peptides / pharmacology
  • Piperidines / chemistry*
  • Piperidines / metabolism*
  • Piperidines / pharmacology
  • Protein Conformation
  • Receptors, Opioid / chemistry*
  • Receptors, Opioid / metabolism*
  • Receptors, Opioid, kappa / chemistry
  • Receptors, Opioid, kappa / metabolism
  • Spiro Compounds / chemistry*
  • Spiro Compounds / metabolism*
  • Spiro Compounds / pharmacology
  • Substrate Specificity

Substances

  • (Nphe(1),Arg(14),Lys(15))N-OFQ NH(2)
  • 1-benzyl-N-(3-(spiroisobenzofuran-1(3H),4'-piperidin-1-yl)propyl)pyrrolidine-2-carboxamide
  • Ligands
  • Narcotic Antagonists
  • Opioid Peptides
  • Piperidines
  • Receptors, Opioid
  • Receptors, Opioid, kappa
  • Spiro Compounds
  • nociceptin receptor

Associated data

  • PDB/4EA3