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PDBsum entry 1ouk
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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 p38alpha map kinase quinazolinone and pyridol-Pyrimidine inhibitor specificity.
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Authors
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C.E.Fitzgerald,
S.B.Patel,
J.W.Becker,
P.M.Cameron,
D.Zaller,
V.B.Pikounis,
S.J.O'Keefe,
G.Scapin.
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Ref.
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Nat Struct Biol, 2003,
10,
764-769.
[DOI no: ]
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PubMed id
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Abstract
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The quinazolinone and pyridol-pyrimidine classes of p38 MAP kinase inhibitors
have a previously unseen degree of specificity for p38 over other MAP kinases.
Comparison of the crystal structures of p38 bound to four different compounds
shows that binding of the more specific molecules is characterized by a peptide
flip between Met109 and Gly110. Gly110 is a residue specific to the alpha, beta
and gamma isoforms of p38. The delta isoform and the other MAP kinases have
bulkier residues in this position. These residues would likely make the peptide
flip energetically unfavorable, thus explaining the selectivity of binding. To
test this hypothesis, we constructed G110A and G110D mutants of p38 and measured
the potency of several compounds against them. The results confirm that the
selectivity of quinazolinones and pyridol-pyrimidines results from the presence
of a glycine in position 110. This unique mode of binding may be exploited in
the design of new p38 inhibitors.
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Figure 2.
Figure 2. Binding of inhibitors to p38  .
Stereo view of the binding sites for the complexes of p38
with (a) compound 1, yellow; (b) compound 2, green24; (c)
compound 3, blue; (d) compound 4, magenta. The same coloring
scheme is used in all figures. Figures 1b and 2 -4 were prepared
with RIBBONS39.
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Figure 4.
Figure 4. Binding orientation of
3,4-dihydropyridol[3,2-d]pyrimidine and 2(1H)-quinazolinone to
p38 .
Surface representation of the inhibitor-binding site: the
linker region is red, the glycine-rich loop blue. Compounds 2
(green)24 and 4 (magenta) are shown with their molecular surface
outlined.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2003,
10,
764-769)
copyright 2003.
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Secondary reference #1
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Title
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Design and synthesis of potent, Selective, And orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-Activated protein kinase.
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Authors
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N.J.Liverton,
J.W.Butcher,
C.F.Claiborne,
D.A.Claremon,
B.E.Libby,
K.T.Nguyen,
S.M.Pitzenberger,
H.G.Selnick,
G.R.Smith,
A.Tebben,
J.P.Vacca,
S.L.Varga,
L.Agarwal,
K.Dancheck,
A.J.Forsyth,
D.S.Fletcher,
B.Frantz,
W.A.Hanlon,
C.F.Harper,
S.J.Hofsess,
M.Kostura,
J.Lin,
S.Luell,
E.A.O'Neill,
S.J.O'Keefe.
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Ref.
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J Med Chem, 1999,
42,
2180-2190.
[DOI no: ]
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PubMed id
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