The structure of the neuropeptide bradykinin bound to the human G-protein coupled receptor bradykinin B2 as determined by solid-state NMR spectroscopy
The structure of the neuropeptide bradykinin bound to the human G-protein coupled receptor bradykinin B2 as determined by solid-state NMR spectroscopy
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DOI：
10.1002/anie.200704282
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Glaubitz, Clemens
中科院分区：
文献类型：
--
作者：
Lopez, Jakob J.;Shukla, Arun K.;Glaubitz, Clemens
G 蛋白偶联受体 (GPCR) 负责大量的生理过程，例如感觉转导、激素活性的介导和细胞间通讯。[1, 2] GPCR 是具有七个跨膜螺旋的膜蛋白，是约 50% 现代药物的靶标。它们构成了已知最大的蛋白质家族，在寻找人类疾病的医学解决方案时已鉴定出 800 多种蛋白质。[3, 4] 然而，由于缺乏三维结构，基于结构的药物设计一直是不可能的。迄今为止，仅解决了两个 GPCR 的结构。[5, 6] 因此，针对 GPCR 的药理学研究主要局限于计算和实验试错方法。[7]通过确定激活 GPCR 的结合激动剂的结构，并将其用作药物设计的结构模板，可以潜在地克服这一限制。为此，需要提高 GPCR 的可用性。[7-9] 在此，我们描述了与人缓激肽 B2 受体结合的激动剂缓激肽的主链结构，这是通过固态 NMR 光谱确定的。这只是此类的第二次详细调查。[10]
G-protein coupled receptors (GPCRs) are responsible for a large number of physiological processes, such as sensory transduction, mediation of hormonal activity, and cell-to-cell communication.[1, 2] GPCRs are membrane proteins with seven transmembrane helices and are the target of some 50% of modern drugs. They constitute the largest known protein family and have had more than 800 species identified in the search for medical solutions to human illnesses.[3, 4] However, owing to the lack of three-dimensional structures, structure-based drug design has not been possible. To date, the structures of only two GPCRs have been solved.[5, 6] Pharmacological research aimed at GPCRs is therefore restricted to mostly computational and experimental trialand-error approaches.[7] This limitation could be potentially overcome by determining the structures of bound agonists, which activate GPCRs, and using these as structural templates for drug design. To do so, the availability of GPCRs needs to be increased.[7–9] Herein, we describe the backbone structure of the agonist bradykinin bound to the human bradykinin B2 receptor, which was determined by solid-state NMR spectroscopy. This is only the second detailed investigation of its kind.[10]