Activation of the α2B adrenoceptor by the sedative sympatholytic dexmedetomidine.,Nature Chemical Biology

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Activation of the α2B adrenoceptor by the sedative sympatholytic dexmedetomidine.
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2020-03-09 , DOI: 10.1038/s41589-020-0492-2
Daopeng Yuan _{1,

2,

3} , Zhongmin Liu _{1,

2,

4,

5} , Jonas Kaindl ₆ , Shoji Maeda ₇ , Jiawei Zhao _{1,

2,

3} , Xiaoou Sun _{1,

2,

3} , Jun Xu _{1,

2,

3} , Peter Gmeiner ₆ , Hong-Wei Wang _{1,

2,

4,

5} , Brian K Kobilka _{1,

2,

3,

7,

8}

Affiliation

The α2 adrenergic receptors (α2ARs) are G protein-coupled receptors (GPCRs) that respond to adrenaline and noradrenaline and couple to the Gi/o family of G proteins. α2ARs play important roles in regulating the sympathetic nervous system. Dexmedetomidine is a highly selective α2AR agonist used in post-operative patients as an anxiety-reducing, sedative medicine that decreases the requirement for opioids. As is typical for selective αAR agonists, dexmedetomidine consists of an imidazole ring and a substituted benzene moiety lacking polar groups, which is in contrast to βAR-selective agonists, which share an ethanolamine group and an aromatic system with polar, hydrogen-bonding substituents. To better understand the structural basis for the selectivity and efficacy of adrenergic agonists, we determined the structure of the α2BAR in complex with dexmedetomidine and Go at a resolution of 2.9 Å by single-particle cryo-EM. The structure reveals the mechanism of α2AR-selective activation and provides insights into Gi/o coupling specificity.

中文翻译：

镇静性交感药物右美托咪定激活α2B肾上腺素能受体。

α2肾上腺素受体（α2ARs）是G蛋白偶联受体（GPCR），可响应肾上腺素和去甲肾上腺素并偶联至G蛋白的Gi / o家族。α2ARs在调节交感神经系统中起重要作用。右美托咪定是一种高度选择性的α2AR激动剂，可在术后患者中用作减轻焦虑的镇静药物，可减少对阿片类药物的需求。如选择性αAR激动剂的典型代表那样，右美托咪啶由咪唑环和缺少极性基团的取代苯部分组成，这与βAR选择性激动剂不同，后者具有乙醇胺基和具有极性氢键取代基的芳族体系。为了更好地了解肾上腺素能激动剂的选择性和功效的结构基础，我们通过单粒子冷冻EM确定了与右美托咪定和Go配合使用的α2BAR的结构，分辨率为2.9。该结构揭示了α2AR选择性激活的机制，并提供了对Gi / o偶联特异性的见解。

更新日期：2020-04-24

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