 |
PDBsum entry 3dy7
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Beyond the mek-Pocket: can current mek kinase inhibitors be utilized to synthesize novel type III nckis? does the mek-Pocket exist in kinases other than mek?
|
|
|
Authors
|
|
H.Tecle,
J.Shao,
Y.Li,
M.Kothe,
S.Kazmirski,
J.Penzotti,
Y.H.Ding,
J.Ohren,
D.Moshinsky,
R.Coli,
N.Jhawar,
E.Bora,
S.Jacques-O'Hagan,
J.Wu.
|
|
|
Ref.
|
|
Bioorg Med Chem Lett, 2009,
19,
226-229.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
An approach and preliminary results for utilizing legacy MEK inhibitors as
templates for a reiterative structural based design and synthesis of novel, type
III NCKIs (non-classical kinase inhibitors) is described. Evidence is provided
that the MEK-pocket or pockets closely related to it may exist in kinases other
than MEK.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
Structures of human map kinase kinase 1 (mek1) and mek2 describe novel noncompetitive kinase inhibition.
|
|
|
Authors
|
|
J.F.Ohren,
H.Chen,
A.Pavlovsky,
C.Whitehead,
E.Zhang,
P.Kuffa,
C.Yan,
P.Mcconnell,
C.Spessard,
C.Banotai,
W.T.Mueller,
A.Delaney,
C.Omer,
J.Sebolt-Leopold,
D.T.Dudley,
I.K.Leung,
C.Flamme,
J.Warmus,
M.Kaufman,
S.Barrett,
H.Tecle,
C.A.Hasemann.
|
|
|
Ref.
|
|
Nat Struct Mol Biol, 2004,
11,
1192-1197.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Figure 2.
Figure 2. Three-dimensional representations of the ternary
complex of MEK1 bound to PD318088 and MgATP. (a) Two views of
the MEK1 protein kinase structure with the N-terminal lobe on
top, the C-terminal lobe at the bottom and the kinase active
site occupied by MgATP and inhibitor located in the hinge
region. The  -helical
regions of the protein are cyan, the  -sheet
regions are green, the ATP cofactor is pink, the magnesium atom
is magenta and PD318088 is gold. The figures are labeled
according to standard kinase nomenclature and were produced with
Ribbons14, 15, 40. (b) View of the MEK1 active site looking down
through the N terminus. The surface is cut away to reveal the
inhibitor and ATP-binding pocket and is color-coded by
hydrophobicity, with the most hydrophobic regions brown and the
least hydrophobic areas green. (c) Detailed view of the
interactions involved in orienting the inhibitor and MgATP in
the MEK1 structure. The residues located within van der Waals
contact are denoted with arcs, whereas hydrogen bonds or
electrostatic interactions are denoted by dashed lines.
|
|
Figure 3.
Figure 3. Superposition of MEK1 and cAMP-dependent protein
kinase (PKA). (a) Two views of MEK1 superimposed on the
structure of PKA (PDB entry 1CDK). MEK1 is a ribbon diagram in
purple; PKA is a cyan ribbon, and the MEK1 inhibitor and MgATP
are not shown for clarity. Left, standard protein kinase view
showing that MEK1 and the closed form of PKA align well
overall13, 14. Right, the position occupied by helix C in PKA is
filled by the MEK activation loop, whereas helix C of MEK1
shifts by  10
Å toward the N-terminal domain. (b) Close-up view of two
different orientations of the MEK1 and PKA overlay. The two
views show that the change in the position of helix C in MEK1 is
accompanied by the formation of a hydrogen-bonding interaction
between the catalytic Glu114 and Ser212. The locations of the
comparable side chains are indicated for PKA. In addition, the
position occupied by helix C of PKA aligns well with the
position of the MEK1 activation loop.
|
|
|
|
|
|
The above figures are
reproduced from the cited reference
with permission from Macmillan Publishers Ltd
|
|
|
|
|
|
|
