Betablockers at work: the crystal structure of the beta2-adrenergic receptor.
Betablockers at work: the crystal structure of the beta2-adrenergic receptor.
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β受体阻滞剂的作用：β2-肾上腺素受体的晶体结构。
DOI：
10.1002/anie.200705971
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发表时间：
2008
影响因子：
--
通讯作者：
F. Hausch
中科院分区：
文献类型：
--
作者：
F. Hausch
G蛋白偶联受体（GPCR）是负责将细胞外信号传递到细胞内的跨膜蛋白。GPCR家族成员超过800个，是最大的信号转导蛋白家族（约3%的人类基因组编码GPCR），[1]并且具有巨大的药理学重要性：超过30%的处方药物靶向GPCR。[2]然而，医学上相关的GPCR只能间接地用于基于结构的药物设计。高分辨率的结构只发表了一个单一的GPCR，光敏视紫红质，[3]这是唯一的GPCR家族，由于其共价连接的辅因子视网膜。为什么GPCR的结构生物学如此具有挑战性？除了真核跨膜蛋白通常遇到的问题，如制备性过表达和纯化，在GPCR的情况下，还缺乏极性接触表面和深刻的构象异质性。[4]Cherezov et al. [5]和Rosenbaum埃塔尔，[6]还有Rasmussen et al. [7]和Day et al. [8]现在已经能够解决典型的配体激活的GPCR的晶体结构。这种GPCR，即β2-肾上腺素能受体，由儿茶酚胺（如肾上腺素和去甲肾上腺素）激活，是β受体阻滞剂和抗哮喘药物的靶点。在这两种情况下，获得的结构是与卡拉唑醇的复合物，卡拉唑醇是一种具有皮摩尔亲和力的部分反向激动剂，可稳定β2-肾上腺素能受体的非活性状态。在这两种情况下，β2-肾上腺素能受体细胞内结构域的进一步硬化是成功的关键。第一种方法是用结构良好的小蛋白T4溶菌酶取代柔性的第三胞内环。在第二种情况下，产生了与第三胞内环的天然膜结合构象结合的抗体。
G-protein-coupled receptors (GPCR) are transmembrane proteins responsible for the transmission of extracellular signals into cells. With more than 800 members, they are the largest family of signal transduction proteins (approximately 3% of the human genome encode GPCRs),[1] and are of enormous pharmacological importance: over 30% of prescribed drugs target a GPCR.[2] Nevertheless, medicinally relevant GPCRs were only indirectly accessible for a structure-based drug design. High-resolution structures had only been published for a single GPCR, the light-sensitive rhodopsin,[3] which is unique among the GPCR family owing to its covalently linked cofactor retinal. Why is the structural biology of GPCRs so challenging? Apart from the problems typically encountered with eukaryotic transmembrane proteins, such as preparative overexpression and purification, in the case of GPCRs, there is also a lack of polar contact surfaces and a profound conformational heterogeneity.[4]Cherezov et al.[5] and Rosenbaum etal.,[6] and also Rasmussen et al.[7] and Day et al.[8] have now been able to solve crystal structures of a typical, ligand-activated GPCR. This GPCR, the β2-adrenergic receptor, is activated by catecholamines, such as adrenaline and noradrenaline, and is the target of betablockers and anti-asthma drugs. In both cases, the structures were obtained as a complex with carazolol, a partial inverse agonist with picomolar affinity, which stabilizes the inactive state of the β2-adrenergic receptor. Further rigidification of the intracellular domain of the β2-adrenergic receptor was critical for success in both cases. This was achieved in the first approach by substitution of the flexible, third intracellular loop by the small, wellstructured protein T4 lysozyme. In the second case, an antibody was generated that binds to a native, membranebound conformation of the third intracellular loop.