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PDBsum entry 3e5a
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References listed in PDB file
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Key reference
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Title
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Modulation of kinase-Inhibitor interactions by auxiliary protein binding: crystallography studies on aurora a interactions with vx-680 and with tpx2.
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Authors
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B.Zhao,
A.Smallwood,
J.Yang,
K.Koretke,
K.Nurse,
A.Calamari,
R.B.Kirkpatrick,
Z.Lai.
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Ref.
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Protein Sci, 2008,
17,
1791-1797.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 2.
Binding of VX-680 in the active site of AurA/TPX2. (A) The
electron density of VX-680 contoured at 1.5[sigma] from the
final 2fo-fc map. The AurA carbons are shown in green, inhibitor
carbons in yellow, oxygens in red, nitrogens in blue, sulfur in
orange, and water molecules in light blue. (B) Interactions of
VX-680 with the active site of AurA when TPX2 is bound. The
backbone tracing is in gray and hydrogen bonds are shown as
dotted black lines. (C) Interactions of VX-680 with the active
site of AurA without TPX2 bound (adapted from Cheetham et al.
2007 and reprinted with permission from Elsevier
[copyright]2007).
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Figure 3.
Superposition of the backbones of AurA/TPX2/VX-680 (gold) and
AurA/TPX2/ADP (gray, pdb: 1ol5) structures focusing on the
different conformations of the glycine-rich loop. The C[alpha]
of Phe144^AUR in the AurA/TPX2/VX-680 structure has moved by >8
A. The VX-680 carbons are in yellow, the ADP carbons in green,
oxygens in red, nitrogens in blue, sulfur and phosphorus in
orange. The side chain of Phe144 is shown in stick form.
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The above figures are
reprinted
from an Open Access publication published by the Protein Society:
Protein Sci
(2008,
17,
1791-1797)
copyright 2008.
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