Molecular control of δ-opioid receptor signalling.
Molecular control of δ-opioid receptor signalling.
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作者：
阿片类药物是广泛使用的处方药和滥用药物，但其信号转导机制尚不清楚。在这里，我们展示了人δ-阿片受体(δ-OR)的1.8o高分辨晶体结构，揭示了钠离子的存在和基础作用，它介导了受体功能选择性和结构活性的变构控制。独特的δ-OR钠离子位点结构位于7-跨膜束核心中的极性相互作用网络中，钠离子稳定激动剂亲和力降低的状态，从而调节信号转导。定点突变和功能研究表明，将变构性钠残基Asn131改变为丙氨酸或缬氨酸可以增强结构性arrestin能信号。Asp95Ala、Asn310Ala和Asn314Ala突变将经典的δ-阿片拮抗剂如纳曲哚转化为有效的β-arrestin偏向激动剂。这些数据为变构钠离子在阿片类药物信号中的控制奠定了分子基础，揭示了钠协调残基在原型G蛋白偶联受体上扮演着“效能开关”的角色。
Opioids represent widely prescribed and abused medications, although their signal transduction mechanisms are not well understood. Here we present the 1.8Å high-resolution crystal structure of the human δ-opioid receptor (δ-OR), revealing the presence and fundamental role of a sodium ion mediating allosteric control of receptor functional selectivity and constitutive activity. The distinctive δ-OR sodium ion site architecture is centrally located in a polar interaction network in the 7-transmembrane bundle core, with the sodium ion stabilizing a reduced agonist affinity state, and thereby modulating signal transduction. Site-directed mutagenesis and functional studies reveal that changing the allosteric sodium site residue Asn131 to alanine or valine augments constitutive arrestin-ergic signaling. Asp95Ala, Asn310Ala, and Asn314Ala mutations transform classical δ-opioid antagonists like naltrindole into potent β-arrestin-biased agonists. The data establish the molecular basis for allosteric sodium ion control in opioid signaling, revealing that sodium-coordinating residues act as “efficacy-switches” at a prototypic G protein-coupled receptor.
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影响因子：
13.8
作者：
Filizola, Marta;Devi, Lakshmi A.
通讯作者：
Devi, Lakshmi A.
DOI：
10.1073/pnas.0710487105
发表时间：
2008-01-08
影响因子：
11.1
作者：
Barnea, Gilad;Strapps, Walter;Lee, Kevin J.
通讯作者：
Lee, Kevin J.
影响因子：
14.8
作者：
通讯作者：
--
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
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
通讯作者：
Zwart PH
影响因子：
64.8
作者：
Granier, Sebastien;Manglik, Aashish;Kruse, Andrew C.;Kobilka, Tong Sun;Thian, Foon Sun;Weis, William I.;Kobilka, Brian K.
通讯作者：
Kobilka, Brian K.