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

Article

关键词: ORL1 RECEPTOR;    ORPHANIN-FQ;    CRYSTALLIZING MEMBRANE;    PROTEIN;    BINDING;    ANTAGONIST;    AGONIST;    SITE;    IDENTIFICATION;    MUTAGENESIS;   

DOI  :  10.1038/nature11085

来源: SCIE

【 摘 要 】

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(1). Although it shares high sequence similarity with classical opioid GPCR subtypes (similar to 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 k (ref. 5) and m (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.

【 授权许可】

Free