Structural insights into µ-opioid receptor activation.
Structural insights into µ-opioid receptor activation.
复制标题
DOI：
10.1038/nature14886
复制
发表时间：
2015-08-20
期刊：
影响因子：
64.8
通讯作者：
Kobilka BK
中科院分区：
文献类型：
--
作者：
Huang W;Manglik A;Venkatakrishnan AJ;Laeremans T;Feinberg EN;Sanborn AL;Kato HE;Livingston KE;Thorsen TS;Kling RC;Granier S;Gmeiner P;Husbands SM;Traynor JR;Weis WI;Steyaert J;Dror RO;Kobilka BK
μ-阿片受体（μOR）的激活是大多数有效镇痛药的作用机制。为了了解μOR活化的结构基础，我们获得了与morphinan激动剂BU72结合并由G蛋白模拟骆驼抗体片段稳定的μOR的2.1 Å x射线晶体结构。bu72稳定的μOR结合袋的变化是微妙的，与β2肾上腺素能受体（β2AR）和M2毒蕈碱受体（M2R）的激动剂结合结构不同。与活性β2AR的比较揭示了μOR核心中三个保守氨基酸的排列重排，分子动力学模拟说明了配体结合口袋是如何与这个保守的三联体构象连接的。此外，配体结合袋和细胞质结构域之间广泛的极性网络似乎在所有三种gpcr的信号传播中起着相似的作用。
Activation of the μ-opioid receptor (μOR) is responsible for the efficacy of the most effective analgesics. To understand the structural basis for μOR activation, we obtained a 2.1 Å X-ray crystal structure of the μOR bound to the morphinan agonist BU72 and stabilized by a G protein-mimetic camelid-antibody fragment. The BU72-stabilized changes in the μOR binding pocket are subtle and differ from those observed for agonist-bound structures of the β2 adrenergic receptor (β2AR) and the M2 muscarinic receptor (M2R). Comparison with active β2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the μOR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three GPCRs.