Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic
- Ferrara
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, {delta}, {kappa} and {mu} ({delta}-OR, {kappa}-OR and {mu}-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 ({approx}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 {kappa} (ref. 5) and {mu} (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.
- Research Organization:
- Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
- Sponsoring Organization:
- OTHERNIH
- OSTI ID:
- 1042494
- Journal Information:
- Nature, Journal Name: Nature Journal Issue: 05, 2012 Vol. 485
- Country of Publication:
- United States
- Language:
- ENGLISH
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