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==Crystal structure of Bos taurus Arp2/3 complex with bound inhibitor CK-666==
==Crystal structure of Bos taurus Arp2/3 complex with bound inhibitor CK-666==
<StructureSection load='3ukr' size='340' side='right' caption='[[3ukr]], [[Resolution|resolution]] 2.48&Aring;' scene=''>
<StructureSection load='3ukr' size='340' side='right'caption='[[3ukr]], [[Resolution|resolution]] 2.48&Aring;' scene=''>
== Structural highlights ==
== 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>
<table><tr><td colspan='2'>[[3ukr]] is a 7 chain structure with sequence from [https://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 [https://proteopedia.org/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>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.48&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CKH:2-FLUORO-N-[2-(2-METHYL-1H-INDOL-3-YL)ETHYL]BENZAMIDE'>CKH</scene></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>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3ukr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ukr OCA], [https://pdbe.org/3ukr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ukr RCSB], [https://www.ebi.ac.uk/pdbsum/3ukr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ukr ProSAT]</span></td></tr>
</table>
</table>
<div style="background-color:#fffaf0;">
== Function ==
== Publication Abstract from PubMed ==
[https://www.uniprot.org/uniprot/ARP3_BOVIN ARP3_BOVIN] Functions as ATP-binding component of the Arp2/3 complex which is involved in regulation of actin polymerization and together with an activating nucleation-promoting factor (NPF) mediates the formation of branched actin networks. Seems to contact the pointed end of the daughter actin filament. Plays a role in ciliogenesis (By similarity).
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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
==See Also==
</div>
*[[Actin-related protein 3D structures|Actin-related protein 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Bos taurus]]
[[Category: Bos taurus]]
[[Category: Han, M]]
[[Category: Large Structures]]
[[Category: Nolen, B J]]
[[Category: Han M]]
[[Category: Atp binding]]
[[Category: Nolen BJ]]
[[Category: Beta-propeller actin fold]]
[[Category: Structural protein]]

Latest revision as of 10:24, 1 March 2024

Crystal structure of Bos taurus Arp2/3 complex with bound inhibitor CK-666

3ukr, resolution 2.48Å

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