Structural basis for selectivity of the isoquinoline sulfonamide family of protein kinase inhibitors.
Structural basis for selectivity of the isoquinoline sulfonamide family of protein kinase inhibitors.
复制标题
蛋白激酶抑制剂异喹啉磺酰胺家族选择性的结构基础。
DOI：
10.1073/pnas.93.13.6308
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发表时间：
1996
影响因子：
11.1
通讯作者：
Cheng,X
中科院分区：
文献类型：
--
作者：
Xu,RM;Carmel,G;Kuret,J;Cheng,X
一大类异喹啉磺酰胺类化合物通过与三磷酸腺苷(ATP)竞争抑制蛋白激酶，而对其他使用ATP的酶如ATPase和腺苷环化酶的活性几乎没有干扰。一种这样的化合物，N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide(CK17)，对从各种来源分离的酪蛋白激酶-1具有选择性。在这里，我们报道了裂殖酵母Pombe Casein Kinase-1与CK17络合的催化域的晶体结构，在2.5埃分辨率下，其结晶R因子为17.8%。这种结构为揭示ATP竞争抑制的机制以及它们对不同蛋白激酶的选择性的来源提供了新的见解。与其他酶相比，蛋白激酶的选择性是通过疏水接触和与异喹啉环的氢键实现的。我们认为，与异喹啉的N-2环原子有关的氢键必须保留，但环可以翻转取决于环5和8上的化学取代基。对蛋白激酶家族个别成员的选择性主要是通过与这些取代基相互作用实现的。
A large family of isoquinoline sulfonamide compounds inhibits protein kinases by competing with adenosine triphosphates(ATP), yet interferes little with the activity of other ATP-using enzymes such as ATPases and adenylate cyclases. One such compound, N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide (CK17), is selective for casein kinase-1 isolated from a variety of sources. Here we report the crystal structure of the catalytic domain of Schizosaccharomyces pombe casein kinase-1 complexed with CK17, refined to a crystallographic R-factor of 17.8% at 2.5 angstrom resolution. The structure provides new insights into the mechanism of the ATP-competing inhibition and the origin of their selectivity toward different protein kinases. Selectivity for protein kinases versus other enzymes is achieved by hydrophobic contacts and the hydrogen bond with isoquinoline ring. We propose that the hydrogen bond involving the ring nitrogen-2 atom of the isoquinoline must be preserved, but that the ring can flip depending on the chemical substituents at ring positions 5 and 8. Selectivity for individual members of the protein kinase family is achieved primarily by interactions with these substituents.