Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.
Nature. 2011 Jan 13;469(7329):175-80. doi: 10.1038/nature09648.
G protein coupled receptors (GPCRs) exhibit a spectrum of functional behaviours in response to natural and synthetic ligands. Recent crystal structures provide insights into inactive states of several GPCRs. Efforts to obtain an agonist-bound active-state GPCR structure have proven difficult due to the inherent instability of this state in the absence of a G protein. We generated a camelid antibody fragment (nanobody) to the human β(2) adrenergic receptor (β(2)AR) that exhibits G protein-like behaviour, and obtained an agonist-bound, active-state crystal structure of the receptor-nanobody complex. Comparison with the inactive β(2)AR structure reveals subtle changes in the binding pocket; however, these small changes are associated with an 11 Å outward movement of the cytoplasmic end of transmembrane segment 6, and rearrangements of transmembrane segments 5 and 7 that are remarkably similar to those observed in opsin, an active form of rhodopsin. This structure provides insights into the process of agonist binding and activation.
G 蛋白偶联受体 (GPCRs) 对天然和合成配体表现出一系列功能行为。最近的晶体结构为几种 GPCR 的非活性状态提供了深入了解。由于在没有 G 蛋白的情况下该状态固有不稳定，因此获得激动剂结合的活性状态 GPCR 结构的努力证明是困难的。我们生成了针对人β(2)肾上腺素能受体 (β(2)AR) 的骆驼科抗体片段（纳米抗体），该抗体表现出 G 蛋白样行为，并获得了受体-纳米抗体复合物的激动剂结合的活性状态晶体结构。与非活性的β(2)AR 结构的比较显示出结合口袋中的细微变化；然而，这些小的变化与跨膜片段 6 的细胞质末端的 11Å 向外运动以及跨膜片段 5 和 7 的重排有关，这些变化与视蛋白（视紫红质的活性形式）中观察到的变化非常相似。该结构提供了关于激动剂结合和激活过程的见解。
