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

Aaron A. Thompson, Wei Liu, Eugene Chun, Vsevolod Katritch, Huixian Wu, Eyal Vardy, Xi Ping Huang, Claudio Trapella, Remo Guerrini, Girolamo Calo, Bryan L. Roth, Vadim Cherezov, Raymond C. Stevens

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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 (∼460%), 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.

Original languageEnglish (US)
Pages (from-to)395-399
Number of pages5
JournalNature
Volume485
Issue number7398
DOIs
StatePublished - May 17 2012

ASJC Scopus subject areas

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    Thompson, A. A., Liu, W., Chun, E., Katritch, V., Wu, H., Vardy, E., Huang, X. P., Trapella, C., Guerrini, R., Calo, G., Roth, B. L., Cherezov, V., & Stevens, R. C. (2012). Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature, 485(7398), 395-399. https://doi.org/10.1038/nature11085