阿片受体家族成员同属于G蛋白偶联受体(G-protein-coupled receptors,GPCRs),遍布外周和中枢神经系统,在痛觉和止痛中起着很关键的角色。
20世纪七八十年代,经典的阿片受体(δ-OR, κ-OR 和 μ-OR)的药理标准已被描述。与其不同,阿片受体样受体(nociceptin/orphanin FQ peptide receptor,NOP)是在最近的阿片受体克隆过程中而被意外发现。
虽然孤啡肽受体与经典阿片受体有60%同源性,但它具有不同的药理学特征。它被内源的孤啡肽(N/OFQ)激活,并对外源配基有独特的选择性。
5月16日,Nature在线发表了美国斯克里普斯研究所分子生物系等科研机构的一篇题为Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic的研究论文,解析了肽类似物拮抗剂复合体-24中人孤啡肽受体的晶体结构,并揭示了孤啡肽受体-配基识别和选择性结合的精细结构。
复合物-24的晶体结构呈现了NOP选择的肽类似物UFP-101(孤啡肽的近似衍生物)的前四个氨基末端残基,为结合这些肽的结构基础提供了重要线索。X射线晶体结构展示了NOP和经典阿片受体(κ-OR和μ-OR)结合口袋的构象差异,这种差异可能是少量的不同残基所致。
NOP复合物-24的晶体结构解释了NOP的选择性机制,并为设计NOP配基提供了新的结构模板。 (生物谷Bioon.com)
doi:10.1038/nature11085
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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.