3ukr: Difference between revisions
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[[ | ==Crystal structure of Bos taurus Arp2/3 complex with bound inhibitor CK-666== | ||
<StructureSection load='3ukr' size='340' side='right' caption='[[3ukr]], [[Resolution|resolution]] 2.48Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3ukr]] is a 7 chain structure with sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UKR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3UKR FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CKH:2-FLUORO-N-[2-(2-METHYL-1H-INDOL-3-YL)ETHYL]BENZAMIDE'>CKH</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3uku|3uku]], [[3ule|3ule]]</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=3ukr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ukr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ukr RCSB], [http://www.ebi.ac.uk/pdbsum/3ukr PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
CK-666 (1) is a recently discovered small-molecule inhibitor of the actin-related protein 2/3 (Arp2/3) complex, a key actin cytoskeleton regulator with roles in bacterial pathogenesis and cancer cell motility. Although 1 is commercially available, the crystal structure of Arp2/3 complex with 1 bound has not been reported, making its mechanism of action uncertain. Furthermore, its relatively low potency increases its potential for off-target effects in vivo, complicating interpretation of its influence in cell biological studies and precluding its clinical use. Herein we report the crystal structure of 1 bound to Arp2/3 complex, which reveals that 1 binds between the Arp2 and Arp3 subunits to stabilize the inactive conformation of the complex. Based on the crystal structure, we used computational docking and free-energy perturbation calculations of monosubstituted derivatives of 1 to guide optimization efforts. Biochemical assays of ten newly synthesized compounds led to the identification of compound 2, which exhibits a threefold increase in inhibitory activity in vitro relative to 1. In addition, our computational analyses unveiled a surface groove at the interface of the Arp2 and Arp3 subunits that can be exploited for additional structure-based optimization. | |||
Structural characterization and computer-aided optimization of a small-molecule inhibitor of the Arp2/3 complex, a key regulator of the actin cytoskeleton.,Baggett AW, Cournia Z, Han MS, Patargias G, Glass AC, Liu SY, Nolen BJ ChemMedChem. 2012 Jul;7(7):1286-94. doi: 10.1002/cmdc.201200104. Epub 2012 May, 23. PMID:22623398<ref>PMID:22623398</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
== | __TOC__ | ||
</StructureSection> | |||
[[Category: Bos taurus]] | [[Category: Bos taurus]] | ||
[[Category: Han, M | [[Category: Han, M]] | ||
[[Category: Nolen, B J | [[Category: Nolen, B J]] | ||
[[Category: Atp binding]] | [[Category: Atp binding]] | ||
[[Category: Beta-propeller actin fold]] | [[Category: Beta-propeller actin fold]] | ||
[[Category: Structural protein]] | [[Category: Structural protein]] | ||
