Structure of the Nociceptin/Orphanin FQ Receptor in Complex with a Peptide Mimetic

Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Nature (Impact Factor: 41.46). 05/2012; 485(7398):395-9. DOI: 10.1038/nature11085
Source: PubMed


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.

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    • "Small-molecule antagonists targeting NOP are under intense investigation for their use as antidepressants (Gavioli and Calo, 2013), while NOP agonists have shown promise as powerful analgesics that lack abuse liability (Lin and Ko, 2013). The crystal structure of human NOP in complex with the potent antagonist Banyu Compound- 24 (C-24) was recently solved to a resolution of 3.0 A ˚ , revealing the first atomic details of the receptor as well as specific contacts made by C-24 within the orthosteric binding site (Thompson et al., 2012). "
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    ABSTRACT: Understanding the mechanism by which ligands affect receptor conformational equilibria is key in accelerating membrane protein structural biology. In the case of G protein-coupled receptors (GPCRs), we currently pursue a brute-force approach for identifying ligands that stabilize receptors and facilitate crystallogenesis. The nociceptin/orphanin FQ peptide receptor (NOP) is a member of the opioid receptor subfamily of GPCRs for which many structurally diverse ligands are available for screening. We observed that antagonist potency is correlated with a ligand's ability to induce receptor stability (Tm) and crystallogenesis. Using this screening strategy, we solved two structures of NOP in complex with top candidate ligands SB-612111 and C-35. Docking studies indicate that while potent, stabilizing antagonists strongly favor a single binding orientation, less potent ligands can adopt multiple binding modes, contributing to their low Tm values. These results suggest a mechanism for ligand-aided crystallogenesis whereby potent antagonists stabilize a single ligand-receptor conformational pair.
    Structure 11/2015; DOI:10.1016/j.str.2015.07.024 · 5.62 Impact Factor
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    • "The GPCR knowledge base has recently benefitted from many well-designed studies uncovering unknown characteristics and mechanisms of action, spatial-temporal dynamics, and detailed insight into structure-function relationships(Chung et al., 2011; Kahsai et al., 2011; Rasmussen et al., 2011; Bock et al., 2014; Lane et al., 2014; Motta-Mena et al., 2014). In particular, the crystal structure of NOPR was recently solved in complex with a peptide mimetic of the selective antagonist UFP-101, itself a close derivative of nociceptin(Thompson et al., 2012). However, there is still a dearth of information pertaining to the intricacies of the NOPR signal transduction system. "
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    ABSTRACT: Comprehensive studies that consolidate selective ligands, quantitative comparisons of G-protein versus arrestin2/3 coupling, together with structure-activity relationship models (SAR) for G-protein coupled receptor (GPCR) systems are less commonly employed. Here we examine biased signaling at the nociceptin/orphanin FQ opioid receptor (NOPR), the most recently identified member of the opioid receptor family. Using real-time, live-cell assays we've identified the signaling profiles of several NOPR-selective ligands in upstream GPCR signaling (G-protein and arrestin pathways), in order to determine their relative transduction coefficients and signaling bias. Complementing this analysis, we designed novel ligands based on the NOPR antagonist J-113,397 to explore structure activity relationships. Our study shows that NOPR is capable of biased signaling, and further the NOPR selective ligands MCOPPB and NNC 63-0532 are G-protein biased agonists. Additionally, minor structural modification of J-113,397 can dramatically shift signaling from antagonist to partial agonist activity. We explore these findings with in silico modeling of binding poses. This work is the first to demonstrate functional selectivity and identification of biased ligands at the nociceptin opioid receptor. The American Society for Pharmacology and Experimental Therapeutics.
    Molecular pharmacology 07/2015; 88(3). DOI:10.1124/mol.115.099150 · 4.13 Impact Factor
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    • "The several recent crystal structures that show interacting parallel receptors in the crystal unit cell (Fig. 3) have been used as an argument in favor of GPCR dimerization, although the possibility exists that these are crystallographic artifacts and/or they do not necessarily represent physiologically relevant interfaces. Two of the five available opioid receptor crystal structures (Fenalti et al., 2014; Granier et al., 2012; Manglik et al., 2012; Thompson et al., 2012; Wu et al., 2012), specifically the structures of μ (Manglik et al., 2012) and κ (Wu et al., 2012) receptors, also reveal parallel arrangements of interacting receptors. As shown in Fig. 3, these correspond to two different interfaces in the case of μ receptor, one of which is also seen in the κ receptor crystal "
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    ABSTRACT: Opioid receptors are important drug targets for pain management, addiction, and mood disorders. Although substantial research on these important subtypes of G protein-coupled receptors has been conducted over the past two decades to discover ligands with higher specificity and diminished side effects, currently used opioid therapeutics remain suboptimal. Luckily, recent advances in structural biology of opioid receptors provide unprecedented insights into opioid receptor pharmacology and signaling. We review here a few recent studies that have used the crystal structures of opioid receptors as a basis for revealing mechanistic details of signal transduction mediated by these receptors, and for the purpose of drug discovery. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmacology 05/2015; 763. DOI:10.1016/j.ejphar.2015.05.012 · 2.53 Impact Factor
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