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

• Published in: Nature (London) Vol. 485; no. 7398; pp. 395 - 399
• Main Authors: Thompson, Aaron A., Liu, Wei, Chun, Eugene, Katritch, Vsevolod, Wu, Huixian, Vardy, Eyal, Huang, Xi-Ping, Trapella, Claudio, Guerrini, Remo, Calo, Girolamo, Roth, Bryan L., Cherezov, Vadim, Stevens, Raymond C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17-05-2012; Nature Publishing Group
• Subjects: 631/154/309/2144; 631/45/535; 631/45/882; 639/638/45/475; Analytical, structural and metabolic biochemistry; Binding Sites; Biological and medical sciences; Biomimetic Materials - chemistry; Biomimetic Materials - metabolism; Biomimetic Materials - pharmacology; Cell receptors; Cell structures and functions; Central nervous system; Chemokines; Cloning; Crystal structure; Crystallography, X-Ray; Fundamental and applied biological sciences. Psychology; HEK293 Cells; Humanities and Social Sciences; Humans; letter; Ligands; Methods; Miscellaneous; Models, Molecular; Molecular and cellular biology; multidisciplinary; Narcotic Antagonists; Nociceptin Receptor; Opioid Peptides - chemistry; Opioid Peptides - metabolism; Opioid Peptides - pharmacology; Peptides; Pharmacology; Piperidines - chemistry; Piperidines - metabolism; Piperidines - pharmacology; Protein Conformation; Receptors, Opioid - chemistry; Receptors, Opioid - metabolism; Receptors, Opioid, kappa - chemistry; Receptors, Opioid, kappa - metabolism; Science; Science (multidisciplinary); Spiro Compounds - chemistry; Spiro Compounds - metabolism; Spiro Compounds - pharmacology; Substrate Specificity; Peptides; Biological receptor
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11085

The crystal structure of the human nociceptin/orphanin FQ peptide receptor in complex with the peptide mimetic antagonist compound-24 is determined, with potential importance for the development of new therapeutic agents.
Where opiates hit home
Four papers in this issue of
Nature
present the long-awaited high-resolution crystal structures of the four known opioid receptors in ligand-bound conformations. These G-protein-coupled receptors are the targets of a broad range of drugs, including painkillers, antidepressants, anti-anxiety agents and anti-addiction medications. Brian Kobilka’s group reports the crystal structure of the µ-opioid receptor bound to a morphinan antagonist and the δ-opioid receptor bound to naltrindole. Raymond Stevens’ group reports on the κ-opioid receptor bound to the selective antagonist JDTic, and the nociceptin/orphanin FQ receptor bound to a peptide mimetic. In an associated News and Views, Marta Filizola and Lakshmi Devi discuss the implications of these landmark papers for research on the mechanisms underlying receptor function and drug development.
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
1
. 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
2
,
3
. 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.