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

Academic Article
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Overview

related to degree

  • Wu, Huixian, Ph.D. in Chemistry, Scripps Research 2010 - 2014
  • Chun, Eugene Patrick, Ph.D. in Chemical Biology, Scripps Research 2007 - 2012

authors

  • Thompson, A. A.
  • Liu, W.
  • Chun, Eugene Patrick
  • Katritch, Vsevolod
  • Wu, Huixian
  • Vardy, E.
  • Huang, X. P.
  • Trapella, C.
  • Guerrini, R.
  • Calo, G.
  • Roth, B. L.
  • Cherezov, Vadim
  • Stevens, Raymond

publication date

  • May 2012

journal

  • Nature  Journal

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.

subject areas

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

PubMed Central ID

  • PMC3356928

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature11085

PubMed ID

  • 22596163
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Additional Document Info

start page

  • 395

end page

  • 399

volume

  • 485

issue

  • 7398

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