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PDBsum entry 3lbl
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References listed in PDB file
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Key reference
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Title
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Structures of low molecular weight inhibitors bound to mdmx and mdm2 reveal new approaches for p53-Mdmx/mdm2 antagonist drug discovery.
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Authors
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G.M.Popowicz,
A.Czarna,
S.Wolf,
K.Wang,
W.Wang,
A.Dömling,
T.A.Holak.
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Ref.
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Cell Cycle, 2010,
9,
1104-1111.
[DOI no: ]
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PubMed id
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Abstract
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Intensive anticancer drug discovery efforts have been made to develop small
molecule inhibitors of the p53-MDM2 and p53-MDMX interactions. We present here
the structures of the most potent inhibitors bound to MDM2 and MDMX that are
based on the new imidazo-indole scaffold. In addition, the structure of the
recently reported spiro-oxindole inhibitor bound to MDM2 is described. The
structures indicate how the substituents of a small molecule that bind to the
three subpockets of the MDM2/X-p53 interaction should be optimized for effective
binding to MDM2 and/or MDMX. While the spiro-oxindole inhibitor triggers
significant ligand-induced changes in MDM2, the imidazo-indoles share similar
binding modes for MDMX and MDM2, but cause only minimal induced-fit changes in
the structures of both proteins. Our study includes the first structure of the
complex between MDMX and a small molecule and should aid in developing efficient
scaffolds for binding to MDMX and/or MDM2.
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