
本研究では、キナーゼ立体構造変化を追跡するKinConレポーターシステムを用いて、BRAF、LKB1、RIPK1、CDK4/6などの疾患関連キナーゼの立体構造ダイナミクスを解明した。キナーゼの活性化状態は、変異、翻訳後修飾、タンパク質相互作用、低分子化合物結合によって大きく変化することが示された。


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Protein kinases act as central molecular switches in the control of cellular functions. Alterations in the regulation and function of protein kinases may provoke diseases including cancer. In this study we investigate the conformational states of such disease-associated kinases using the high sensitivity of the Kinase Conformation (KinCon)-reporter system. We ﬁrst track BRAF-kinase activity conformation changes upon melanoma drug binding. Second, we also use the KinCon reporter technology to examine the impact of regulatory protein interactions on LKB1-kinase tumor suppressor functions. Third, we explore the conformational dynamics of RIP-kinases in response to TNF-pathway activation and small molecule interactions. Finally, we show that CDK4/6 interactions with regulatory proteins alter conformations which remain unaffected in the presence of clinically applied inhibitors. Apart from its predictive value, the KinCon technology helps to identify cellular factors that impact drug efficacies. The understanding of the structural dynamics of full-length protein kinases when interacting with small molecule inhibitors or regulatory proteins is crucial for designing more effective therapeutic strategies.

### Competing Interest Statement

E.S and P.T. are co-founders of KinCon biolabs

Kinases in motion: impact of protein and small molecule interactions on kinase conformations

疾患関連キナーゼの構造ダイナミクス-タンパク質および低分子化合物の相互作用がキナーゼの立体構造に及ぼす影響


疾患関連キナーゼの構造ダイナミクス：タンパク質および低分子化合物の相互作用がキナーゼの立体構造に及ぼす影響
