Structural Basis for the Inhibition of Cyclin G‐Associated Kinase by Gefitinib
| العنوان: | Structural Basis for the Inhibition of Cyclin G‐Associated Kinase by Gefitinib |
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| المؤلفون: | Miyuki Kato-Murayama, Tamami Uejima, Naomi Ohbayashi, Hiroshi Nojima, Mutsuko Kukimoto-Niino, Shigeyuki Yokoyoma, Noboru Ohsawa, Kazutaka Murayama, Mikako Shirouzu, Takayoshi Matsuda |
| المصدر: | ChemistryOpen, Vol 7, Iss 9, Pp 713-719 (2018) ChemistryOpen |
| بيانات النشر: | Wiley-VCH, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, gefitinib, medicine.disease_cause, Virus, lcsh:Chemistry, 03 medical and health sciences, Gefitinib, complex structures, medicine, Epidermal growth factor receptor, Binding site, neoplasms, Cyclin, Mutation, protein kinases, biology, Full Paper, Chemistry, Kinase, General Chemistry, Full Papers, novel binding sites, inhibitor development, Cell biology, respiratory tract diseases, 030104 developmental biology, Protein kinase domain, lcsh:QD1-999, biology.protein, medicine.drug |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 2191-1363 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2272832e711352642fc0dcbcd43db963 https://doaj.org/article/1792a4ab9ff142d693f1b4b82f51f702 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....2272832e711352642fc0dcbcd43db963 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 21911363 |
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