Crystal structures of catalytic subunit of cAMP-dependent protein kinase in complex with isoquinolinesulfonyl protein kinase inhibitors H7, H8, and H89 - Structural implications for selectivity
Crystal structures of catalytic subunit of cAMP-dependent protein kinase in complex with isoquinolinesulfonyl protein kinase inhibitors H7, H8, and H89 - Structural implications for selectivity
复制标题
DOI：
10.1074/jbc.271.42.26157
复制
发表时间：
1996-10-18
影响因子：
4.8
通讯作者：
Bossemeyer, D
中科院分区：
文献类型：
--
作者：
Engh, RA;Girod, A;Bossemeyer, D
发现了数百种不同的蛋白激酶参与高度多样化的细胞信号传导途径，这与已知的细胞信号传导调节剂的数量少得多形成鲜明对比，其中，H系列蛋白激酶抑制剂（1-（5-异喹啉磺酰基）-2-甲基哌嗪（H7），N-[2-（methylamino）-ethyl]-5-isoquinolinesulfonamide（H8）N-[2-（p-Bromo-cinnamoamino）ethyl]-5-isoquinolinesulfonamide（H89））在细胞调节的研究中经常用于阻断信号传导途径。为了阐明在原子分辨率的抑制机制，并使基于结构的药物设计的潜在的治疗信号通路的调节剂，我们确定了相应的复合物与cAPK催化亚基的晶体结构。与H7和H8（2.2埃）和与H89（2.3埃）的复合物定义了异喹啉-磺酰胺衍生物在ATP结合位点的结合模式，同时证明了配体诱导的结构变化的影响。酶和抑制剂之间的特异性相互作用包括异喹啉环氮连接到瓦尔-123的骨架酰胺和抑制剂侧链酰胺键合到Glu-170的骨架羰基。蛋白激酶的ATP结合位点的保守性允许评价控制这些抑制剂在激酶中的一般选择性的因素。这些结果将有助于设计具有特定性质的蛋白激酶抑制剂。
The discovery of several hundred different protein kinases involved in highly diverse cellular signaling pathways is in stark contrast to the much smaller number of known modulators of cell signaling, Of these, the H series protein kinase inhibitors (1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7), N-[2-(methylamino)-ethyl]-5-isoquinolinesulfonamide (H8) N-[2-(p-Bromo-cinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89)) are frequently used to block signaling pathways in studies of cellular regulation. To elucidate inhibition mechanisms at atomic resolution and to enable structure-based drug design of potential therapeutic modulators of signaling pathways, we determined the crystal structures of corresponding complexes with the cAPK catalytic subunit. Complexes with H7 and H8 (2.2 Angstrom) and with H89 (2.3 Angstrom) define the binding mode of the isoquinoline-sulfonamide derivatives in the ATP-binding site while demonstrating effects of ligand-induced structural change. Specific interactions between the enzyme and the inhibitors include the isoquinoline ring nitrogen ligating to backbone amide of Val-123 and an inhibitor side chain amide bonding to the backbone carbonyl of Glu-170. The conservation of the ATP-binding site of protein kinases allows evaluation of factors governing general selectivity of these inhibitors among kinases. These results should assist efforts in the design of protein kinase inhibitors with specific properties.