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PDBsum entry 1dm2
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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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Inhibition of cyclin-Dependent kinases, Gsk-3beta and ck1 by hymenialdisine, A marine sponge constituent.
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Authors
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L.Meijer,
A.M.Thunnissen,
A.W.White,
M.Garnier,
M.Nikolic,
L.H.Tsai,
J.Walter,
K.E.Cleverley,
P.C.Salinas,
Y.Z.Wu,
J.Biernat,
E.M.Mandelkow,
S.H.Kim,
G.R.Pettit.
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Ref.
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Chem Biol, 2000,
7,
51-63.
[DOI no: ]
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PubMed id
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Abstract
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BACKGROUND: Over 2000 protein kinases regulate cellular functions. Screening for
inhibitors of some of these kinases has already yielded some potent and
selective compounds with promising potential for the treatment of human
diseases. RESULTS: The marine sponge constituent hymenialdisine is a potent
inhibitor of cyclin-dependent kinases, glycogen synthase kinase-3beta and casein
kinase 1. Hymenialdisine competes with ATP for binding to these kinases. A
CDK2-hymenialdisine complex crystal structure shows that three hydrogen bonds
link hymenialdisine to the Glu81 and Leu83 residues of CDK2, as observed with
other inhibitors. Hymenialdisine inhibits CDK5/p35 in vivo as demonstrated by
the lack of phosphorylation/down-regulation of Pak1 kinase in E18 rat cortical
neurons, and also inhibits GSK-3 in vivo as shown by the inhibition of MAP-1B
phosphorylation. Hymenialdisine also blocks the in vivo phosphorylation of the
microtubule-binding protein tau at sites that are hyperphosphorylated by GSK-3
and CDK5/p35 in Alzheimer's disease (cross-reacting with Alzheimer's-specific
AT100 antibodies). CONCLUSIONS: The natural product hymenialdisine is a new
kinase inhibitor with promising potential applications for treating
neurodegenerative disorders.
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Figure 2.
Figure 2. Inhibition of CDK1/cyclin B by HD analogues.
CDK1/cyclin B was assayed as described in the Supplementary
material section. Activity is presented as% of maximal activity
(i.e. in the absence of inhibitors).
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Figure 8.
Figure 8. Protein–inhibitor interactions in the CDK2–HD
complex. (a) Stereo diagram showing the refined structure of HD
in the ATP-binding pocket of CDK2. Inferred hydrogen bonds are
shown as thin dotted lines. Oxygen atoms are shown in red,
nitrogen atoms in blue and bromine in green. (b) Schematic
illustration of the interactions between CDK2 and HD. Protein
sidechain contacts are indicated by lines connecting to the
respective residue box, whereas interactions with mainchain
atoms are shown as lines to the specific mainchain atom. Van der
Waals contacts are indicated by dotted lines and hydrogen bonds
by broken lines.
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The above figures are
reprinted
by permission from Cell Press:
Chem Biol
(2000,
7,
51-63)
copyright 2000.
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Secondary reference #1
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Title
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Exploiting chemical libraries, Structure, And genomics in the search for kinase inhibitors.
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Authors
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N.S.Gray,
L.Wodicka,
A.M.Thunnissen,
T.C.Norman,
S.Kwon,
F.H.Espinoza,
D.O.Morgan,
G.Barnes,
S.Leclerc,
L.Meijer,
S.H.Kim,
D.J.Lockhart,
P.G.Schultz.
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Ref.
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Science, 1998,
281,
533-538.
[DOI no: ]
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PubMed id
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Figure 1.
Fig. 1. (A) Scheme for the combinatorial synthesis of
2,6,9-trisubstituted purines from a 2-, 6-, or 9-linked purine
scaffold^ with amination and alkylation chemistries. Chemical
structures of CDK inhibitors (B) flavopiridol (C) olomoucine^
and roscovitine, and (D) purvalanol A and B and (E) 52 and 52Me.
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Figure 2.
Fig. 2. (A) Purvalanol B bound to CDK2 (black sticks,
principal conformation only) is compared with bound (1)
olomoucine^ (white sticks) and bound roscovitine (orange
sticks), (2) bound flavopiridol (green sticks), and (3) bound
ATP (yellow sticks). The comparisons are based on superposition
of the C  atoms of
CDK2. The ligands are shown in ball-and-stick representation
with carbon atoms colored white, nitrogen atoms colored blue,
oxygen atoms colored red, phosphorous atoms colored violet, and^
the chlorine atom of purvalanol colored green. (B) Schematic^
drawing of CDK2-purvalanol B interactions. Protein side chain
contacts are indicated by lines connecting the respective
residue^ box and interactions to main chain atoms are shown as
lines to the specific main chain atoms. Van der Waals contacts
are indicated^ by thin dotted lines, and H bonds by dashed
lines. For H bonds the distances between the nonhydrogen atoms
are indicated in angstroms. W, water.
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The above figures are
reproduced from the cited reference
with permission from the AAAs
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Secondary reference #2
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Title
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Inhibition of cyclin-Dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine.
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Authors
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W.F.De azevedo,
S.Leclerc,
L.Meijer,
L.Havlicek,
M.Strnad,
S.H.Kim.
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Ref.
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Eur J Biochem, 1997,
243,
518-526.
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PubMed id
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Secondary reference #3
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Title
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Multiple modes of ligand recognition: crystal structures of cyclin-Dependent protein kinase 2 in complex with ATP and two inhibitors, Olomoucine and isopentenyladenine.
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Authors
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U.Schulze-Gahmen,
J.Brandsen,
H.D.Jones,
D.O.Morgan,
L.Meijer,
J.Vesely,
S.H.Kim.
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Ref.
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Proteins, 1995,
22,
378-391.
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PubMed id
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Secondary reference #4
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Title
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Crystal structure of cyclin-Dependent kinase 2.
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Authors
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H.L.De bondt,
J.Rosenblatt,
J.Jancarik,
H.D.Jones,
D.O.Morgan,
S.H.Kim.
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Ref.
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Nature, 1993,
363,
595-602.
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PubMed id
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