5y80
Complex structure of cyclin G-associated kinase with gefitinib
Structural highlights
FunctionGAK_HUMAN Associates with cyclin G and CDK5. Seems to act as an auxilin homolog that is involved in the uncoating of clathrin-coated vesicles by Hsc70 in non-neuronal cells. Expression oscillates slightly during the cell cycle, peaking at G1.[1] Publication Abstract from PubMedGefitinib 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 nanobodyGAK 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. Structural Basis for the Inhibition of Cyclin G-Associated Kinase by Gefitinib.,Ohbayashi N, Murayama K, Kato-Murayama M, Kukimoto-Niino M, Uejima T, Matsuda T, Ohsawa N, Yokoyoma S, Nojima H, Shirouzu M ChemistryOpen. 2018 Sep 10;7(9):721-727. doi: 10.1002/open.201800177. eCollection, 2018 Sep. PMID:30214852[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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