3UO4

Aurora A in complex with RPM1680

Summary for 3UO4

• Entry DOI: 10.2210/pdb3uo4/pdb
• Related: 3UNJ 3UNK 3UNZ 3UO5 3UO6 3UOD 3UOH 3UOJ 3UOK 3UOL 3UP2 3UP7
• Descriptor: Aurora kinase A, 4-{[4-(biphenyl-2-ylamino)pyrimidin-2-yl]amino}benzoic acid, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: protein kinase, aurora a, inhibitor, dfg-in, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytoskeleton, centrosome: O14965
• Total number of polymer chains: 1
• Total formula weight: 32927.74

Authors

Martin, M.P.,Zhu, J.-Y.,Schonbrunn, E. (deposition date: 2011-11-16, release date: 2012-01-25, Last modification date: 2023-09-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.45 Å)