Structure of the δ-opioid receptor bound to naltrindole.
Structure of the δ-opioid receptor bound to naltrindole.
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DOI：
10.1038/nature11111
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发表时间：
2012-05-16
期刊：
影响因子：
64.8
通讯作者：
Kobilka, Brian K.
中科院分区：
文献类型：
--
作者：
Granier, Sebastien;Manglik, Aashish;Kruse, Andrew C.;Kobilka, Tong Sun;Thian, Foon Sun;Weis, William I.;Kobilka, Brian K.
阿片受体家族包括三个成员，即µ-阿片受体、δ-阿片受体和κ-阿片受体，它们对吗啡和海洛因等经典阿片生物碱以及内啡肽等内源性多肽配体产生反应。它们属于G蛋白偶联受体(GPCR)超家族，是控制疼痛的极佳治疗靶点。δ阿片受体(δ-OR)在镇痛以及其他神经功能中发挥作用，但目前对此知之甚少。最近解决了µ-OR和κ-OR的结构。在这里，我们报告了小鼠δ-OR的晶体结构，它与亚型选择性拮抗剂纳曲吲哚结合。连同µ-OR和κ-OR的结构，δ-OR结构提供了对阿片配体识别的保守元件的洞察，同时也揭示了与配体亚型选择性相关的结构特征。阿片受体的结合口袋可以分为两个不同的区域。尽管这个口袋的下半部分在阿片受体中高度保守，但上半部分包含具有亚型选择性的分歧残基。这为阿片受体药理学的“消息-地址”模型提供了结构性的解释和验证，在该模型中，不同的“消息”(疗效)和“地址”(选择性)决定因素包含在单个配体中。将δ-OR的地址区域与其他GPCRs进行比较发现，这种结构组织可能是一种更普遍的现象，也延伸到其他GPCRs家族。
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 understood. The structures of the µ-OR and κ-OR have recently been solved,. 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.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1073/pnas.78.10.6543
发表时间：
1981-01-01
期刊：
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影响因子：
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作者：
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通讯作者：
GOLDSTEIN, A
影响因子：
4.8
作者：
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通讯作者：
O'Dowd, BF
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
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作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
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Zwart PH
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
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作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC