Tautermann Christofer S, Pautsch Alexander
Lead Identification and Optimization Support, Boehringer Ingelheim Pharma GmbH & Co. KG , 88397 Biberach an der Riss, Germany.
ACS Med Chem Lett. 2011 Mar 31;2(6):414-8. doi: 10.1021/ml100247s. eCollection 2011 Jun 9.
The very recently published first X-ray structure of the β2 adrenergic receptor in its active state hosting a small molecule (PDB ID: 3P0G) reveals a lot of information about the G-protein-coupled receptor (GPCR) activation process from a structural point of view. When compared to the inactive state crystal structure of β2, large differences are seen in the GPCR helical structure at the cytoplasmatic side, whereas very subtle changes occur at the ligand binding site. The observation that there are hardly any differences in the binding site of agonists and inverse agonists implies that in silico predictions of the efficacy of ligands will be very hard. This is illustrated by the example of an already published binding mode of a β2 agonist, which has been modeled into the inactive state X-ray structure of the β2 receptor. When comparing the modeled structure to the new activated X-ray structure, quantitative agreement of the binding mode is found, implying that the subtle changes between agonist binding to the activated state and inverse agonist binding to the inactive state can currently not be captured by standard in silico modeling methods.
最近发表的β2肾上腺素能受体处于结合小分子的活性状态下的首个X射线结构（蛋白质数据库ID：3P0G），从结构角度揭示了许多关于G蛋白偶联受体（GPCR）激活过程的信息。与β2的非活性状态晶体结构相比，在细胞质侧的GPCR螺旋结构中可观察到巨大差异，而在配体结合位点则发生非常细微的变化。激动剂和反向激动剂结合位点几乎没有差异这一观察结果表明，对配体功效进行计算机模拟预测将非常困难。已发表的一种β2激动剂结合模式的例子说明了这一点，该模式已被模拟到β2受体的非活性状态X射线结构中。将模拟结构与新的活化X射线结构进行比较时，发现结合模式存在定量一致性，这意味着目前标准的计算机模拟方法无法捕捉到激动剂与活化状态结合和反向激动剂与非活性状态结合之间的细微变化。
