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4u58

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Revision as of 15:10, 10 May 2019

IMPORTIN-ALPHA MINOR NLS SITE INHIBITOR

Structural highlights

4u58 is a 1 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	Kpna2, Rch1 (LK3 transgenic mice)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[IMA1_MOUSE] Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus.

Publication Abstract from PubMed

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-alpha interaction. Importin-alpha 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-alpha, 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.

Selective Targeting of the TPX2 Site of Importin-alpha Using Fragment-Based Ligand Design.,Holvey RS, Valkov E, Neal D, Stewart M, Abell C ChemMedChem. 2015 Apr 20. doi: 10.1002/cmdc.201500014. PMID:25899172^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Holvey RS, Valkov E, Neal D, Stewart M, Abell C. Selective Targeting of the TPX2 Site of Importin-alpha Using Fragment-Based Ligand Design. ChemMedChem. 2015 Apr 20. doi: 10.1002/cmdc.201500014. PMID:25899172 doi:http://dx.doi.org/10.1002/cmdc.201500014

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4u58"

@@ Line 1: / Line 1: @@
 ==IMPORTIN-ALPHA MINOR NLS SITE INHIBITOR==
-<StructureSection load='4u58' size='340' side='right' caption='[[4u58]], [[Resolution|resolution]] 2.56&Aring;' scene=''>
+<StructureSection load='4u58' size='340' side='right'caption='[[4u58]], [[Resolution|resolution]] 2.56&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4u58]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4U58 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4U58 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4u58]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4U58 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4U58 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3C6:N~2~-[4-(PYRIDIN-3-YL)BENZOYL]-L-LYSINAMIDE'>3C6</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Kpna2, Rch1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4u58 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4u58 OCA], [http://pdbe.org/4u58 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4u58 RCSB], [http://www.ebi.ac.uk/pdbsum/4u58 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4u58 ProSAT]</span></td></tr>
 </table>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
+[[Category: Lk3 transgenic mice]]
 [[Category: Holvey, R S]]
 [[Category: Stewart, M]]

4u58

From Proteopedia

Revision as of 15:10, 10 May 2019

IMPORTIN-ALPHA MINOR NLS SITE INHIBITOR

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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