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PDBsum entry 4u54
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Transport protein
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PDB id
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4u54
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References listed in PDB file
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Key reference
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Title
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Selective targeting of the tpx2 site of importin-α Using fragment-Based ligand design.
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Authors
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R.S.Holvey,
E.Valkov,
D.Neal,
M.Stewart,
C.Abell.
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Ref.
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Chemmedchem, 2015,
10,
1232-1239.
[DOI no: ]
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PubMed id
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Abstract
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Protein-protein interactions are difficult therapeutic targets, and inhibiting
pathologically relevant interactions without disrupting other essential ones
presents an additional challenge. Herein we report how this might be achieved
for the potential anticancer target, the TPX2-importin-α interaction.
Importin-α is a nuclear transport protein that regulates the spindle assembly
protein TPX2. It has two binding sites-major and minor-to which partners bind.
Most nuclear transport cargoes use the major site, whereas TPX2 binds
principally to the minor site. Fragment-based approaches were used to identify
small molecules that bind importin-α, and crystallographic studies identified a
lead series that was observed to bind specifically to the minor site,
representing the first ligands specific for this site. Structure-guided
synthesis informed the elaboration of these fragments to explore the source of
ligand selectivity between the minor and major sites. These ligands are starting
points for the development of inhibitors of this protein-protein interaction.
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