Ohbayashi Naomi, Murayama Kazutaka, Kato-Murayama Miyuki, Kukimoto-Niino Mutsuko, Uejima Tamami, Matsuda Takayoshi, Ohsawa Noboru, Yokoyoma Shigeyuki, Nojima Hiroshi, Shirouzu Mikako
Division of Structural and Synthetic Biology RIKEN Center for Life Science Technologies 1-7-22 Suehiro-cho, Tsurumi Yokohama 230-0045 Japan.
RIKEN Center for Biosystems Dynamics Research 1-7-22 Suehiro-cho, Tsurumi Yokohama 230-0045 Japan.
ChemistryOpen. 2018 Sep 10;7(9):721-727. doi: 10.1002/open.201800177. eCollection 2018 Sep.
Gefitinib is the molecular target drug for advanced non-small-cell lung cancer. The primary target of gefitinib is the positive mutation of epidermal growth factor receptor, but it also inhibits cyclin G-associated kinase (GAK). To reveal the molecular bases of GAK and gefitinib binding, structure analyses were conducted and determined two forms of the gefitinib-bound nanobody⋅GAK kinase domain complex structures. The first form, GAK_1, has one gefitinib at the ATP binding pocket, whereas the second form, GAK_2, binds one each in the ATP binding site and a novel binding site adjacent to the activation segment C-terminal helix, a unique element of the Numb-associated kinase family. In the novel binding site, gefitinib binds in the hydrophobic groove around the activation segment, disrupting the conserved hydrogen bonds for the catalytic activity. These structures suggest possibilities for the development of selective GAK inhibitors for viral infections, such as the hepatitis C virus.
吉非替尼是用于晚期非小细胞肺癌的分子靶向药物。吉非替尼的主要靶点是表皮生长因子受体的阳性突变，但它也抑制细胞周期蛋白G相关激酶（GAK）。为揭示GAK与吉非替尼结合的分子基础，进行了结构分析并确定了两种吉非替尼结合的纳米抗体⋅GAK激酶结构域复合物结构形式。第一种形式GAK_1在ATP结合口袋处有一个吉非替尼，而第二种形式GAK_2在ATP结合位点和与激活片段C末端螺旋相邻的一个新结合位点各结合一个吉非替尼，该螺旋是Numb相关激酶家族的独特元件。在新结合位点，吉非替尼结合在激活片段周围的疏水凹槽中，破坏了催化活性所需的保守氢键。这些结构为开发用于病毒感染（如丙型肝炎病毒）的选择性GAK抑制剂提供了可能性。
