3E5A

Crystal structure of Aurora A in complex with VX-680 and TPX2

Summary for 3E5A

• Entry DOI: 10.2210/pdb3e5a/pdb
• Descriptor: Serine/threonine-protein kinase 6, Targeting protein for Xklp2, CYCLOPROPANECARBOXYLIC ACID {4-[4-(4-METHYL-PIPERAZIN-1-YL)-6-(5-METHYL-2H-PYRAZOL-3-YLAMINO)-PYRIMIDIN-2-YLSULFANYL]-PHENYL}-AMIDE, ... (5 entities in total)
• Functional Keywords: aurora a, serine/threonine-protein kinase, cofactor, tpx2, vx-680, inhibitor, phosphorylation, atp-binding, cell cycle, nucleotide-binding, phosphoprotein, transferase, nucleus
• Biological source: Homo sapiens; More
• Cellular location: Cytoplasm, cytoskeleton, centrosome: O14965; Nucleus: Q9ULW0
• Total number of polymer chains: 2
• Total formula weight: 36718.54

Authors

Zhao, B.,Smallwood, A.,Lai, Z. (deposition date: 2008-08-13, release date: 2008-10-28, Last modification date: 2024-10-30)

Primary citation

Zhao, B.,Smallwood, A.,Yang, J.,Koretke, K.,Nurse, K.,Calamari, A.,Kirkpatrick, R.B.,Lai, Z.
Modulation of kinase-inhibitor interactions by auxiliary protein binding: crystallography studies on Aurora A interactions with VX-680 and with TPX2.
Protein Sci., 17:1791-1797, 2008

PubMed Abstract: VX-680, also known as MK-0457, is an ATP-competitive small molecule inhibitor of the Aurora kinases that has entered phase II clinical trials for the treatment of cancer. We have solved the cocrystal structure of AurA/TPX2/VX-680 at 2.3 A resolution. In the crystal structure, VX-680 binds to the active conformation of AurA. The glycine-rich loop in AurA adopts a unique bent conformation, forming a pi-pi interaction with the phenyl group of VX-680. In contrast, in the published AurA/VX-680 structure, VX-680 binds to AurA in the inactive conformation, interacting with a hydrophobic pocket only present in the inactive conformation. These data suggest that TPX2, a protein cofactor, can alter the binding mode of VX-680 with AurA. More generally, the presence of physiologically relevant cofactor proteins can alter the kinetics, binding interactions, and inhibition of enzymes, and studies with these multiprotein complexes may be beneficial to the discovery and optimization of enzyme inhibitors as therapeutic agents.

PubMed: 18662907
DOI: 10.1110/ps.036590.108

Experimental method

X-RAY DIFFRACTION (2.3 Å)