A Novel Mechanism by Which Small Molecule Inhibitors Induce the DFG Flip in Aurora A

详细信息    查看全文

• 作者：Mathew P. Martin ; Jin-Yi Zhu ; Harshani R. Lawrence ; Roberta Pireddu ; Yunting Luo ; Riazul Alam ; Sevil Ozcan ; Said M. Sebti ; Nicholas J. Lawrence ; Ernst Sch枚nbrunn
• 刊名：ACS Chemical Biology
• 出版年：2012
• 出版时间：April 20, 2012
• 年：2012
• 卷：7
• 期：4
• 页码：698-706
• 全文大小：581K
• 年卷期：v.7,no.4(April 20, 2012)
• ISSN：1554-8937

文摘

Most protein kinases share a DFG (Asp-Phe-Gly) motif in the ATP site that can assume two distinct conformations, the active DFG-in and the inactive DFG-out states. Small molecule inhibitors able to induce the DFG-out state have received considerable attention in kinase drug discovery. Using a typical DFG-in inhibitor scaffold of Aurora A, a kinase involved in the regulation of cell division, we found that halogen and nitrile substituents directed at the N-terminally flanking residue Ala273 induced global conformational changes in the enzyme, leading to DFG-out inhibitors that are among the most potent Aurora A inhibitors reported to date. The data suggest an unprecedented mechanism of action, in which induced-dipole forces along the Ala273 side chain alter the charge distribution of the DFG backbone, allowing the DFG to unwind. As the ADFG sequence and three-dimensional structure is highly conserved, DFG-out inhibitors of other kinases may be designed by specifically targeting the flanking alanine residue with electric dipoles.