PDBsum entry 4u5v

Transport protein

PDB id: 4u5v

Contents

Protein chain

426 a.a.

Ligands

RH2 ×2

Waters ×295

PDB id:

4u5v

Name:

Transport protein

Title:

Importin-alpha minor nls site inhibitor

Structure:

Importin subunit alpha-1. Chain: a. Fragment: unp residues 72-497. Synonym: importin alpha p1,karyopherin subunit alpha-2,pendulin,pore targeting complex 58 kda subunit,ptac58,rag cohort protein 1,srp1- alpha. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: kpna2, rch1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.97Å R-factor: 0.231 R-free: 0.259

Authors:

M.Stewart,E.Valkov,R.S.Holvey

Key ref:

R.S.Holvey et al. (2015). Selective Targeting of the TPX2 Site of Importin-α Using Fragment-Based Ligand Design. Chemmedchem, 10, 1232-1239. PubMed id: 25899172 DOI: 10.1002/cmdc.201500014

Date:

25-Jul-14 Release date: 13-May-15

Protein chain

P52293  (IMA1_MOUSE) -  Importin subunit alpha-1 from Mus musculus

Seq: 529 a.a.

Struc: 426 a.a.

DOI no: 10.1002/cmdc.201500014

Chemmedchem 10:1232-1239 (2015)

PubMed id: 25899172

Selective Targeting of the TPX2 Site of Importin-α Using Fragment-Based Ligand Design.

R.S.Holvey, E.Valkov, D.Neal, M.Stewart, C.Abell.

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.