| http://purl.uniprot.org/citations/22623398 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/22623398 | http://www.w3.org/2000/01/rdf-schema#comment | "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."xsd:string |
| http://purl.uniprot.org/citations/22623398 | http://purl.org/dc/terms/identifier | "doi:10.1002/cmdc.201200104"xsd:string |
| http://purl.uniprot.org/citations/22623398 | http://purl.uniprot.org/core/author | "Han M.S."xsd:string |
| http://purl.uniprot.org/citations/22623398 | http://purl.uniprot.org/core/author | "Liu S.Y."xsd:string |
| http://purl.uniprot.org/citations/22623398 | http://purl.uniprot.org/core/author | "Nolen B.J."xsd:string |
| http://purl.uniprot.org/citations/22623398 | http://purl.uniprot.org/core/author | "Patargias G."xsd:string |
| http://purl.uniprot.org/citations/22623398 | http://purl.uniprot.org/core/author | "Baggett A.W."xsd:string |
| http://purl.uniprot.org/citations/22623398 | http://purl.uniprot.org/core/author | "Cournia Z."xsd:string |
| http://purl.uniprot.org/citations/22623398 | http://purl.uniprot.org/core/author | "Glass A.C."xsd:string |
| http://purl.uniprot.org/citations/22623398 | http://purl.uniprot.org/core/date | "2012"xsd:gYear |
| http://purl.uniprot.org/citations/22623398 | http://purl.uniprot.org/core/name | "ChemMedChem"xsd:string |
| http://purl.uniprot.org/citations/22623398 | http://purl.uniprot.org/core/pages | "1286-1294"xsd:string |
| http://purl.uniprot.org/citations/22623398 | http://purl.uniprot.org/core/title | "Structural characterization and computer-aided optimization of a small-molecule inhibitor of the Arp2/3 complex, a key regulator of the actin cytoskeleton."xsd:string |
| http://purl.uniprot.org/citations/22623398 | http://purl.uniprot.org/core/volume | "7"xsd:string |
| http://purl.uniprot.org/citations/22623398 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/22623398 |
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