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PDBsum entry 2zmc
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References listed in PDB file
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Key reference
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Title
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Crystal structure of the catalytic domain of the mitotic checkpoint kinase mps1 in complex with sp600125.
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Authors
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M.L.Chu,
L.M.Chavas,
K.T.Douglas,
P.A.Eyers,
L.Tabernero.
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Ref.
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J Biol Chem, 2008,
283,
21495-21500.
[DOI no: ]
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PubMed id
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Abstract
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Chromosomal instability can result from defective control of checkpoints and is
associated with malignant cell growth. Monopolar spindle 1 (Mps1) is a
dual-specificity protein kinase that has important roles in the prevention of
aneuploidy during the cell cycle and might therefore be a potential target for
new therapeutic agents in the treatment of cancer. To gain insights into the
molecular mechanism of Mps1 inhibition by small molecules, we determined the
x-ray structure of Mps1, both alone and in complex with the ATP-competitive
inhibitor SP600125. Mps1 adopts a classic protein kinase fold, with the
inhibitor sitting in the ATP-binding site where it is stabilized by hydrophobic
interactions. We identified a secondary pocket, not utilized by SP600125, which
might be exploited for the rational design of specific Mps1 inhibitors. These
structures provide important insights into the interaction of this protein
kinase with small molecules and suggest potential mechanisms for Mps1 regulation.
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Figure 2.
FIGURE 2. Overall structure of human Mps1 catalytic domain.
A, ribbon representation of the structure of Mps1 kinase domain.
Characteristic key features important for substrate binding and
catalysis are labeled as follows: glycine loop (orange),  C helix,
catalytic loop (cyan), and activation loop with DFG motif (blue)
and p + 1 loop (purple). B, comparison of Mps1 apo-WT (green)
and T686A (brown) with phosphorylated Aurora A (P-ArA, red, PDB
ID 1OL5) and unphosphorylated Aurora A (unP-ArA, gray, PDB ID
1MUO). Displacement of helix C, due to the conformation of the
activation loop in the unphosphorylated structures, results in a
shift of the glutamic acid residue and loss of interaction with
the catalytically important lysine. C, superposition of the p +
1 loop between WT apo-kinase (green) and T686A-SP600125 complex
(gold). The positions of Thr-686 and Ala-686 are indicated.
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Figure 3.
FIGURE 3. Structural insights of the SP600125-binding site.
A, detailed view of the structure of T686A-SP600125 complex,
showing SP600125 bound in the ATP-binding site. The residues
that interact with SP600125 are depicted as sticks. The 2F[o] -
F[c] map around SP600125 is shown, contoured at 1.5  . B,
surface representation (stereo view) of the inhibitor-binding
site in Mps1 and JNK1 (PDB ID 1UKI [PDB]
) with SP600125 shown in yellow. Important differences in the
composition and orientation of key residues
(Mps1^Lys-553/JNK1^Lys-55, Mps1^Cys-604/JNK1^Leu-110,
Mps1^Tyr-591/JNK1^Ile-106, Mps1^Tyr-568, Mps1^Glu-571,
JNK1^Glu-73, JNK1^Met-77, Mps1^Met-602/JNK1^Met-108, and
Mps1^Ile-663/JNK1^Leu-168) can be exploited for the rational
design of Mps1-specific inhibitors. C, surface representation of
the SP600125-binding site in human Mps1. A molecule of PEG from
the crystallization solution is bound in a secondary pocket next
to the catalytic Lys-553.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2008,
283,
21495-21500)
copyright 2008.
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