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PDBsum entry 3mss
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Transferase/transferase inhibitor
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PDB id
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3mss
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References listed in PDB file
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Key reference
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Title
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Binding or bending: distinction of allosteric abl kinase agonists from antagonists by an nmr-Based conformational assay.
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Authors
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W.Jahnke,
R.M.Grotzfeld,
X.Pellé,
A.Strauss,
G.Fendrich,
S.W.Cowan-Jacob,
S.Cotesta,
D.Fabbro,
P.Furet,
J.Mestan,
A.L.Marzinzik.
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Ref.
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J Am Chem Soc, 2010,
132,
7043-7048.
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PubMed id
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Abstract
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Allosteric inhibitors of Bcr-Abl have emerged as a novel therapeutic option for
the treatment of CML. Using fragment-based screening, a search for novel Abl
inhibitors that bind to the myristate pocket was carried out. Here we show that
not all myristate ligands are functional inhibitors, but that the conformational
state of C-terminal helix_I is a structural determinant for functional activity.
We present an NMR-based conformational assay to monitor the conformation of this
crucial helix_I and show that myristate ligands that bend helix_I are functional
antagonists, whereas ligands that bind to the myristate pocket but do not induce
this conformational change are kinase agonists. Activation of c-Abl by
allosteric agonists has been confirmed in a biochemical assay.
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