Crystal structure of the human angiotensin II type 2 receptor bound to an angiotensin II analog
Crystal structure of the human angiotensin II type 2 receptor bound to an angiotensin II analog
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DOI：
10.1038/s41594-018-0079-8
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发表时间：
2018-07-01
影响因子：
16.8
通讯作者：
Iwata, So
中科院分区：
文献类型：
--
作者：
Asada, Hidetsugu;Horita, Shoichiro;Iwata, So
血管紧张素II（AngII）在调节人体血压中起着重要作用，其主要通过AngII与G蛋白偶联受体（GPCRs）AngII 1型受体（AT（1）R）和AngII 2型受体（AT（2）R）之间的相互作用介导。我们已经在3.2埃分辨率下解析了结合肽配体[Sar（1），Ile（8）] AngII及其特异性抗体的人AT2R的晶体结构。[Sar（1），Ile（8）] AngII与AT（1）R和AT（2）R的小分子配体结合的“核心”结合结构域和“扩展”结合结构域相互作用，所述“扩展”结合结构域相当于毒蕈碱乙酰胆碱受体的变构调节剂结合位点。我们产生了抗体片段以稳定作为正变构调节剂的延伸结合结构域。我们还确定了一个签名带正电荷的集群，这是保守的肽结合受体，定位在底部的结合口袋的C末端。报道的结果应该有助于设计血管紧张素受体的配体，并可能与其他肽GPCR。
Angiotensin II (AngII) plays a central role in regulating human blood pressure, which is mainly mediated by interactions between AngII and the G-protein-coupled receptors (GPCRs) AngII type 1 receptor (AT(1)R) and AngII type 2 receptor (AT(2)R). We have solved the crystal structure of human AT2R binding the peptide ligand [Sar(1), Ile(8)] AngII and its specific antibody at 3.2-angstrom resolution. [Sar(1), Ile(8)] AngII interacts with both the 'core' binding domain, where the small-molecule ligands of AT(1)R and AT(2)R bind, and the 'extended' binding domain, which is equivalent to the allosteric modulator binding site of muscarinic acetylcholine receptor. We generated an antibody fragment to stabilize the extended binding domain that functions as a positive allosteric modulator. We also identified a signature positively charged cluster, which is conserved among peptide-binding receptors, to locate C termini at the bottom of the binding pocket. The reported results should help with designing ligands for angiotensin receptors and possibly to other peptide GPCRs.