4U5S

IMPORTIN-ALPHA MINOR NLS SITE INHIBITOR

Summary for 4U5S

• Entry DOI: 10.2210/pdb4u5s/pdb
• Descriptor: Importin subunit alpha-1, N-[(2S)-2-[(N~2~-acetyl-D-lysyl)amino]-3-(pyridin-3-ylmethoxy)propyl]-L-allothreonyl-D-phenylalaninamide (3 entities in total)
• Functional Keywords: tpx2. inhibitor, minor site, transport protein
• Biological source: Mus musculus (Mouse)
• Cellular location: Cytoplasm : P52293
• Total number of polymer chains: 1
• Total formula weight: 47343.27

Authors

Stewart, M.,Valkov, E.,Holvey, R.S. (deposition date: 2014-07-25, release date: 2015-05-13, Last modification date: 2024-05-08)

Primary citation

Holvey, R.S.,Valkov, E.,Neal, D.,Stewart, M.,Abell, C.
Selective Targeting of the TPX2 Site of Importin-alpha Using Fragment-Based Ligand Design.
Chemmedchem, 10:1232-1239, 2015

PubMed Abstract: 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.

PubMed: 25899172
DOI: 10.1002/cmdc.201500014

Experimental method

X-RAY DIFFRACTION (2.12 Å)