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PDBsum entry 1nvq
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural basis for chk1 inhibition by ucn-01.
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Authors
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B.Zhao,
M.J.Bower,
P.J.Mcdevitt,
H.Zhao,
S.T.Davis,
K.O.Johanson,
S.M.Green,
N.O.Concha,
B.B.Zhou.
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Ref.
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J Biol Chem, 2002,
277,
46609-46615.
[DOI no: ]
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PubMed id
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Abstract
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Chk1 is a serine-threonine kinase that plays an important role in the DNA damage
response, including G(2)/M cell cycle control. UCN-01 (7-hydroxystaurosporine),
currently in clinical trials, has recently been shown to be a potent Chk1
inhibitor that abrogates the G(2)/M checkpoint induced by DNA-damaging agents.
To understand the structural basis of Chk1 inhibition by UCN-01, we determined
the crystal structure of the Chk1 kinase domain in complex with UCN-01. Chk1
structures with staurosporine and its analog SB-218078 were also determined. All
three compounds bind in the ATP-binding pocket of Chk1, producing only slight
changes in the protein conformation. Selectivity of UCN-01 toward Chk1 over
cyclin-dependent kinases can be explained by the presence of a hydroxyl group in
the lactam moiety interacting with the ATP-binding pocket. Hydrophobic
interactions and hydrogen-bonding interactions were observed in the structures
between UCN-01 and the Chk1 kinase domain. The high structural complementarity
of these interactions is consistent with the potency and selectivity of UCN-01.
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Figure 1.
Fig. 1. A ribbon diagram of the Chk1 kinase domain in
complex with UCN-01. The N-terminal domain is in green, the
C-terminal domain is in yellow, and the activation loop is in
magenta. Elements of secondary structure are numbered from the N
to the C termini accordingly. UCN-01 is shown in a
ball-and-stick presentation: red for oxygen atoms, blue for
nitrogen, and yellow for carbon. All figures were created with
the computer programs MolScript (25) and BobScript (26).
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Figure 5.
Fig. 5. The solvent-accessible surface of the bound
conformation of UCN-01 (purple) is shown with the
solvent-accessible surface of Chk1 (green mesh) in the
Chk1·UCN-01 complex. The shape complementarity between
this rigid inhibitor and the binding site is very high, and the
large amount of non-polar buried surface area in the complex
provides the energy for a very strong interaction.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2002,
277,
46609-46615)
copyright 2002.
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