3UP2

Aurora A in complex with RPM1686

3UP2 の概要

• エントリーDOI: 10.2210/pdb3up2/pdb
• 関連するPDBエントリー: 3UNJ 3UNK 3UNZ 3UO4 3UO5 3UO6 3UOD 3UOH 3UOJ 3UOK 3UOL 3UP7
• 分子名称: Aurora kinase A, 4-[(4-{[2-(trifluoromethoxy)phenyl]amino}pyrimidin-2-yl)amino]benzoic acid, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: protein kinase, aurora a, inhibitor, dfg-in, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytoskeleton, centrosome: O14965
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32873.57

構造登録者

Martin, M.P.,Zhu, J.-Y.,Schonbrunn, E. (登録日: 2011-11-17, 公開日: 2012-01-25, 最終更新日: 2023-09-13)

主引用文献

Martin, M.P.,Zhu, J.Y.,Lawrence, H.R.,Pireddu, R.,Luo, Y.,Alam, R.,Ozcan, S.,Sebti, S.M.,Lawrence, N.J.,Schonbrunn, E.
A Novel Mechanism by Which Small Molecule Inhibitors Induce the DFG Flip in Aurora A.
Acs Chem.Biol., 7:698-706, 2012

PubMed Abstract: 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.

PubMed: 22248356
DOI: 10.1021/cb200508b

実験手法

X-RAY DIFFRACTION (2.3001 Å)