title: Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic.
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.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Thompson
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Eugene
authors.initials: E
authors.lastname: Chun
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
authors.forename: Huixian
authors.initials: H
authors.lastname: Wu
authors.forename: Eyal
authors.initials: E
authors.lastname: Vardy
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.forename: Claudio
authors.initials: C
authors.lastname: Trapella
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calo
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
mesh_terms: D001665:Binding Sites; D040761:Biomimetic Materials / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011487:Protein Conformation; D011957:Receptors, Opioid / Q000737:chemistry* / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000737:chemistry / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D013379:Substrate Specificity; D000094942:Nociceptin Receptor
chemical_list: C479838:(Nphe(1),Arg(14),Lys(15))N-OFQ NH(2); C543193:1-benzyl-N-(3-(spiroisobenzofuran-1(3H),4'-piperidin-1-yl)propyl)pyrrolidine-2-carboxamide; D008024:Ligands; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010880:Piperidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; D000094942:Nociceptin Receptor; C000722283:OPRL1 protein, human