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| | == Structural highlights == | | == Structural highlights == |
| | <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> | | <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" id="ligandDat"><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]] 2.48Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3uku|3uku]], [[3ule|3ule]]</div></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'>[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> | | <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> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/ARPC4_BOVIN ARPC4_BOVIN]] Functions as actin-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 mother actin filament (By similarity). [[https://www.uniprot.org/uniprot/ARPC2_BOVIN ARPC2_BOVIN]] Functions as actin-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 mother actin filament (By similarity). [[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). [[https://www.uniprot.org/uniprot/ARC1B_BOVIN ARC1B_BOVIN]] Functions as 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 (By similarity). [[https://www.uniprot.org/uniprot/ARPC5_BOVIN ARPC5_BOVIN]] Functions as 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 (By similarity). [[https://www.uniprot.org/uniprot/ARP2_BOVIN ARP2_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. [[https://www.uniprot.org/uniprot/ARPC3_BOVIN ARPC3_BOVIN]] Functions as 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 (By similarity).
| + | [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). |
| - | <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>
| + | ==See Also== |
| - | | + | *[[Actin-related protein 3D structures|Actin-related protein 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 3ukr" style="background-color:#fffaf0;"></div>
| + | |
| - | == References ==
| + | |
| - | <references/>
| + | |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | [[Category: Bos taurus]] | | [[Category: Bos taurus]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Han, M]] | + | [[Category: Han M]] |
| - | [[Category: Nolen, B J]] | + | [[Category: Nolen BJ]] |
| - | [[Category: Atp binding]]
| + | |
| - | [[Category: Beta-propeller actin fold]]
| + | |
| - | [[Category: Structural protein]]
| + | |
