Heptares Therapeutics Ltd, BioPark, Welwyn Garden City, Herts, AL7 3AX, UK.
Structure. 2011 Sep 7;19(9):1283-93. doi: 10.1016/j.str.2011.06.014.
Methylxanthines, including caffeine and theophylline, are among the most widely consumed stimulant drugs in the world. These effects are mediated primarily via blockade of adenosine receptors. Xanthine analogs with improved properties have been developed as potential treatments for diseases such as Parkinson's disease. Here we report the structures of a thermostabilized adenosine A(2A) receptor in complex with the xanthines xanthine amine congener and caffeine, as well as the A(2A) selective inverse agonist ZM241385. The receptor is crystallized in the inactive state conformation as defined by the presence of a salt bridge known as the ionic lock. The complete third intracellular loop, responsible for G protein coupling, is visible consisting of extended helices 5 and 6. The structures provide new insight into the features that define the ligand binding pocket of the adenosine receptor for ligands of diverse chemotypes as well as the cytoplasmic regions that interact with signal transduction proteins.
甲基黄嘌呤，包括咖啡因和茶碱，是世界上使用最广泛的兴奋剂药物之一。这些作用主要通过阻断腺苷受体来介导。具有改善特性的黄嘌呤类似物已被开发为治疗帕金森病等疾病的潜在药物。在这里，我们报告了一个热稳定的腺苷 A(2A)受体与黄嘌呤胺同系物和咖啡因的复合物的结构，以及 A(2A)选择性反向激动剂 ZM241385 的结构。该受体以所谓的离子锁存在的非活性状态构象结晶。负责 G 蛋白偶联的完整的第三胞内环可见，由延伸的螺旋 5 和 6 组成。这些结构为不同化学型配体的腺苷受体配体结合口袋的特征以及与信号转导蛋白相互作用的细胞质区域提供了新的见解。
