Structural Basis for the Inhibition of Cyclin G-Associated Kinase by Gefitinib

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• Gefitinib is a targeted therapy for non-small-cell lung cancer, primarily targeting mutated epidermal growth factor receptor.
• Gefitinib also inhibits cyclin G-associated kinase (GAK), a less-explored function.
• Understanding GAK-gefitinib interactions is crucial for exploring new therapeutic applications.

Purpose of the Study:

• To elucidate the molecular mechanisms of gefitinib binding to cyclin G-associated kinase (GAK).
• To determine the structural basis for gefitinib's inhibition of GAK.
• To explore potential therapeutic applications of GAK inhibition.

Main Methods:

• X-ray crystallography was used to determine the complex structures of the nanobody-GAK kinase domain with gefitinib.
• Analysis of two distinct binding modes of gefitinib within the GAK structure.

Main Results:

• Two forms of the gefitinib-bound nanobody⋅GAK kinase domain complex were identified: GAK_1 and GAK_2.
• GAK_1 showed gefitinib binding in the ATP pocket.
• GAK_2 revealed gefitinib binding in both the ATP site and a novel adjacent site, disrupting catalytic activity.

Conclusions:

• The determined structures provide molecular insights into gefitinib-GAK interactions.
• The novel binding site identified offers a unique target for drug development.
• These findings suggest potential for developing selective GAK inhibitors for treating viral infections like hepatitis C virus.