阿片受体家族包含3个(μ-、δ-和κ-阿片受体)成员,他们属于G蛋白偶联受体超家族(GPCR)。 除止痛作用外,δ-阿片受体(δ-OR)在神经学上的其它功能仍不是很清楚。
5月16日,国际著名期刊Nature在线发表了斯坦福大学医学院等科研单位的题为Structure of the δ-opioid receptor bound to naltrindole的研究论文,报道了鼠δ-OR与亚型选择性拮抗剂纳曲吲哚结合的晶体结构。
结构显示,阿片配基的结合口袋可分为两个明显不同的部位:结合口袋的下方在阿片受体中高度保守;上方的氨基酸残基相异,决定亚型选择性。这为阿片受体药剂学的“message–address”模型提供了结构上的解释和证实,在这个模型中,不同的“message”(效力)和“address”(选择性)包含在配基中。
通过比较δ-OR与其它GPCRs的“address”区域显示这个结构组成可能是一个更普遍的现象。(生物谷Bioon.com)
doi:10.1038/nature11111
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PMID:
Structure of the δ-opioid receptor bound to naltrindole
Sébastien Granier,Aashish Manglik,Andrew C. Kruse,Tong Sun Kobilka,Foon Sun Thian,William I. Weis& Brian K. Kobilka
Department of Molecular and Cellular Physiology, Stanford University School of Medicine,Stanford,California 94305, USA
CNRS UMR 5203, and INSERM U661, and Université Montpellier 1 et 2, Institut de Génomique Fonctionnelle, Montpellier 34094, France
Department of Structural Biology, Stanford University School of Medicine, Stanford, California
The opioid receptor family comprises three members, the μ-, δ- and κ-opioid receptors, which respond to classical opioid alkaloids such as morphine and heroin as well as to endogenous peptide ligands like endorphins. They belong to the G-protein-coupled receptor (GPCR) superfamily, and are excellent therapeutic targets for pain control. The δ-opioid receptor (δ-OR) has a role in analgesia, as well as in other neurological functions that remain poorly understood1. The structures of the μ-OR and κ-OR have recently been solved2, 3. Here we report the crystal structure of the mouse δ-OR, bound to the subtype-selective antagonist naltrindole. Together with the structures of the μ-OR and κ-OR, the δ-OR structure provides insights into conserved elements of opioid ligand recognition while also revealing structural features associated with ligand-subtype selectivity. The binding pocket of opioid receptors can be divided into two distinct regions. Whereas the lower part of this pocket is highly conserved among opioid receptors, the upper part contains divergent residues that confer subtype selectivity. This provides a structural explanation and validation for the ‘message–address’ model of opioid receptor pharmacology,in which distinct‘message’ (efficacy) and ‘address’ (selectivity) determinants are contained within a single ligand. Comparison of the address region of the δ-OR with other GPCRs reveals that this structural organization may be a more general phenomenon,extending to other GPCR families as well.