阿片受體家族成員同屬于G蛋白偶聯(lián)受體(G-protein-coupled receptors，GPCRs),，遍布外周和中樞神經(jīng)系統(tǒng),，在痛覺和止痛中起著很關(guān)鍵的角色。
20世紀七八十年代，經(jīng)典的阿片受體(δ-OR,， κ-OR 和 μ-OR)的藥理標準已被描述,。與其不同，阿片受體樣受體(nociceptin/orphanin FQ peptide receptor,，NOP)是在最近的阿片受體克隆過程中而被意外發(fā)現(xiàn),。
雖然孤啡肽受體與經(jīng)典阿片受體有60%同源性，但它具有不同的藥理學特征,。它被內(nèi)源的孤啡肽（N/OFQ）激活,，并對外源配基有獨特的選擇性。
5月16日,，Nature在線發(fā)表了美國斯克里普斯研究所分子生物系等科研機構(gòu)的一篇題為Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic的研究論文,，解析了肽類似物拮抗劑復合體-24中人孤啡肽受體的晶體結(jié)構(gòu)，并揭示了孤啡肽受體-配基識別和選擇性結(jié)合的精細結(jié)構(gòu),。
復合物-24的晶體結(jié)構(gòu)呈現(xiàn)了NOP選擇的肽類似物UFP-101（孤啡肽的近似衍生物）的前四個氨基末端殘基,，為結(jié)合這些肽的結(jié)構(gòu)基礎(chǔ)提供了重要線索。X射線晶體結(jié)構(gòu)展示了NOP和經(jīng)典阿片受體(κ-OR和μ-OR)結(jié)合口袋的構(gòu)象差異,，這種差異可能是少量的不同殘基所致,。
NOP復合物-24的晶體結(jié)構(gòu)解釋了NOP的選擇性機制，并為設(shè)計NOP配基提供了新的結(jié)構(gòu)模板,。 (生物谷Bioon.com)
doi:10.1038/nature11085
PMC:
PMID:
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
Department of Molecular Biology,，The Scripps Research Institute，La Jolla, California 92037,，USA
National Institute of Mental Health Psychoactive Drug Screening Program,，Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry，University of North Carolina Chapel Hill Medical School,，Chapel Hill,，North Carolina 27599, USA
Department of Pharmaceutical Sciences and LTTA (Laboratorio per le Tecnologie delle Terapie Avanzate)，University of Ferrara,，44121 Ferrara,，Italy
Department of Experimental and Clinical Medicine,，Section of Pharmacology and National Institute of Neuroscience， University of Ferrara,，44121 Ferrara,，Italy
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 GPCR1. 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 ligands2,， 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.
