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PDBsum entry 2jdo
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References listed in PDB file
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Key reference
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Title
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A structural comparison of inhibitor binding to pkb, Pka and pka-Pkb chimera.
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Authors
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T.G.Davies,
M.L.Verdonk,
B.Graham,
S.Saalau-Bethell,
C.C.Hamlett,
T.Mchardy,
I.Collins,
M.D.Garrett,
P.Workman,
S.J.Woodhead,
H.Jhoti,
D.Barford.
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Ref.
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J Mol Biol, 2007,
367,
882-894.
[DOI no: ]
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PubMed id
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Abstract
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Although the crystal structure of the anti-cancer target protein kinase B
(PKBbeta/Akt-2) has been useful in guiding inhibitor design, the closely related
kinase PKA has generally been used as a structural mimic due to its facile
crystallization with a range of ligands. The use of PKB-inhibitor
crystallography would bring important benefits, including a more rigorous
understanding of factors dictating PKA/PKB selectivity, and the opportunity to
validate the utility of PKA-based surrogates. We present a
"back-soaking" method for obtaining PKBbeta-ligand crystal structures,
and provide a structural comparison of inhibitor binding to PKB, PKA, and
PKA-PKB chimera. One inhibitor presented here exhibits no PKB/PKA selectivity,
and the compound adopts a similar binding mode in all three systems. By
contrast, the PKB-selective inhibitor A-443654 adopts a conformation in PKB and
PKA-PKB that differs from that with PKA. We provide a structural explanation for
this difference, and highlight the ability of PKA-PKB to mimic the true PKB
binding mode in this case.
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Figure 1.
Figure 1. Chemical structures of 1 (isoquinoline
sulphonamide) and 2 (A-443654).
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Figure 5.
Figure 5. Inhibitor 2 binding to PKA and PKB. (a) PKA-2 and
(b) PKB-2 (in the region of the ATP site). Final 2mF[o]–DF[c]
electron density for the inhibitors is contoured at 1σ and
shown in blue. (c) Superposition of PKA-2 (grey) and PKB-2
(yellow). Residues are labelled using PKB numbering. (d)
Schematic diagram showing binding of 2 to PKA and PKB. Key
non-covalent interactions are depicted as broken lines. The
alternative positions of the indole ring are shown by shading:
PKA (light grey) and PKB (black). (e) Surface representation of
PKB with compound 2 bound. The surface was coloured by
lipophilicity in AstexViewer^46 using the method described by
Gaillard et al.,^53 with red/pink representing the most
lipophilic regions, and blue/green the least lipophilic. The
putative methyl-aromatic interaction discussed in the text is
shown as a broken line. (f) Overlay of surfaces for PKA (grey)
and PKB (yellow) with compound 2 bound. The indole group of 2
packs with the side-chain of Met282, but would leave a cavity in
PKA due to the substitution by leucine at this point in the
active site.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2007,
367,
882-894)
copyright 2007.
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