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PDBsum entry 1q4l
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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 characterization of the gsk-3beta active site using selective and non-Selective ATP-Mimetic inhibitors.
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Authors
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J.A.Bertrand,
S.Thieffine,
A.Vulpetti,
C.Cristiani,
B.Valsasina,
S.Knapp,
H.M.Kalisz,
M.Flocco.
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Ref.
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J Mol Biol, 2003,
333,
393-407.
[DOI no: ]
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PubMed id
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Abstract
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GSK-3beta is a regulatory serine/threonine kinase with a plethora of cellular
targets. Consequently, selective small molecule inhibitors of GSK-3beta may have
a variety of therapeutic uses including the treatment of neurodegenerative
diseases, type II diabetes and cancer. In order to characterize the active site
of GSK-3beta, we determined crystal structures of unphosphorylated GSK-3beta in
complex with selective and non-selective ATP-mimetic inhibitors. Analysis of the
inhibitors' interactions with GSK-3beta in the structures reveals how the enzyme
can accommodate a number of diverse molecular scaffolds. In addition, a
conserved water molecule near Thr138 is identified that can serve a functional
role in inhibitor binding. Finally, a comparison of the interactions made by
selective and non-selective inhibitors highlights residues on the edge of the
ATP binding-site that can be used to obtain inhibitor selectivity. Information
gained from these structures provides a promising route for the design of
second-generation GSK-3beta inhibitors.
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Figure 4.
Figure 4. Diagram showing the binding of (a) AMP-PNP, (b)
staurosporine, (c) indirubin-3-monoxime and (d) alsterpaullone
to GSK-3b. Residues playing a direct or indirect role in
inhibitor binding are shown in a ball-and-stick representation.
Inhibitor molecules are shown in tan; water molecules and Mg2+
are shown in red and yellow, respectively. The C^a trace of
GSK-3b is shown in blue and green for the N- and C-terminal
domains, respectively. To avoid "cluttering" in the AMP-PNP
diagram, the two water molecules coordinating Mg1 are omitted
and Asp200, the residue coordinating Mg1 and Mg2, is unlabelled.
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Figure 6.
Figure 6. Stereo view showing I-5 bound in the GSK-3b
active site. Residues playing a direct or indirect role in
inhibitor binding are shown in a ball-and-stick representation.
I-5 is shown in light brown; chlorine atoms are in green and
water molecules are in red. The C^a trace of GSK-3b is shown in
blue and green for the N- and C-terminal domains, respectively.
For the sake of clarity, Leu132 and Tyr134 are unlabelled and
Val110 has been omitted from the Figure.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2003,
333,
393-407)
copyright 2003.
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