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PDBsum entry 1h1p
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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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Structure-Based design of a potent purine-Based cyclin-Dependent kinase inhibitor.
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Authors
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T.G.Davies,
J.Bentley,
C.E.Arris,
F.T.Boyle,
N.J.Curtin,
J.A.Endicott,
A.E.Gibson,
B.T.Golding,
R.J.Griffin,
I.R.Hardcastle,
P.Jewsbury,
L.N.Johnson,
V.Mesguiche,
D.R.Newell,
M.E.Noble,
J.A.Tucker,
L.Wang,
H.J.Whitfield.
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Ref.
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Nat Struct Biol, 2002,
9,
745-749.
[DOI no: ]
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PubMed id
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Abstract
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Aberrant control of cyclin-dependent kinases (CDKs) is a central feature of the
molecular pathology of cancer. Iterative structure-based design was used to
optimize the ATP- competitive inhibition of CDK1 and CDK2 by
O(6)-cyclohexylmethylguanines, resulting in O(6)-cyclohexylmethyl-2-(4'-
sulfamoylanilino)purine. The new inhibitor is 1,000-fold more potent than the
parent compound (K(i) values for CDK1 = 9 nM and CDK2 = 6 nM versus 5,000 nM and
12,000 nM, respectively, for O(6)-cyclohexylmethylguanine). The increased
potency arises primarily from the formation of two additional hydrogen bonds
between the inhibitor and Asp 86 of CDK2, which facilitate optimum hydrophobic
packing of the anilino group with the specificity surface of CDK2. Cellular
studies with O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino) purine demonstrated
inhibition of MCF-7 cell growth and target protein phosphorylation, consistent
with CDK1 and CDK2 inhibition. The work represents the first successful
iterative synthesis of a potent CDK inhibitor based on the structure of fully
activated CDK2-cyclin A. Furthermore, the potency of
O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino)purine was both predicted and
fully rationalized on the basis of protein-ligand interactions.
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Figure 1.
Figure 1. Inhibitor structures and binding of NU2058 to
T160pCDK2 -cyclinA. a, Chemical structures of NU2058, NU6094,
NU6086 and NU6102. b, T160pCDK2 -cyclinA -NU2058 structure.
T160pCDK2 -cyclinA is drawn in ribbon representation. CDK2 is
purple and cyclin A is gold. NU2058 bound in the CDK2 active
site cleft is shown as a surface representation in green. c,
CDK2 -NU2058 hydrogen bond interactions. Schematic
representation of the conserved hydrogen bonds between backbone
atoms of CDK2 residues Leu 83 and Glu 81, located in the hinge
region, and NU2058. Hydrogen bonds are drawn as dotted lines.
Arrows pointing towards Phe 80 and Lys 89 indicate the
orientation of the inhibitor within the active site.
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Figure 2.
Figure 2. Binding of NU6094, NU6086 and NU6102 to T160pCDK2
-cyclinA. a, T160pCDK2 -cyclinA -NU6094 structure. Selected
CDK2 residues are drawn in ball-and-stick representation, with
carbon atoms colored green (inhibitor) and yellow (CDK2). The
final 2F[o]-F[c] electron density contoured at 0.24 e^- Å-3 for
NU6094 is included. Hydrogen bonds in all panels except (b) are
denoted by dashed lines. b, NU6094 bound to the CDK2 active
site. NU6094 is depicted as yellow CPK spheres. The CDK2
molecular surface is colored by atom type: carbon, oxygen and
nitrogen atoms are green, red and blue, respectively. The figure
illustrates the complementarity of the NU6094 anilino ring to
the shape of the hydrophobic tunnel leading to the specificity
surface. c, T160pCDK2 -cyclinA -NU6086 structure. NU6086 and
selected CDK2 residues are rendered in ball-and
stick-representation, with carbon atoms colored as in (a). Both
conformers of the anilino ring (denoted I and II) are included.
The final 2F[o]-F[c] electron density for NU6086 is contoured at
0.24 e^- Å-3. d, T160pCDK2 -cyclinA -NU6102 structure. NU6102
and selected CDK2 residues are rendered in ball-and-stick
representation, with carbon atoms colored as in (a). The final
2F[o]-F[c] electron density for NU6102 is contoured at 0.24 e^-
Å-3. e, NU6102 bound to the CDK2 active site. The CDK2 molecular
surface is rendered in transparent gray so that interactions
between the NU6102 sulfonamide group and the backbone nitrogen
and side chain oxygen of Asp 86 are visible. Hydrogen bonds are
depicted by dotted lines. NU6102 is rendered in ball and stick,
with carbon atoms colored green.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2002,
9,
745-749)
copyright 2002.
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