3UKR
Crystal structure of Bos taurus Arp2/3 complex with bound inhibitor CK-666
Summary for 3UKR
| Entry DOI | 10.2210/pdb3ukr/pdb |
| Related | 3UKU 3ULE |
| Descriptor | Actin-related protein 3, Actin-related protein 2, Actin-related protein 2/3 complex subunit 1B, ... (9 entities in total) |
| Functional Keywords | beta-propeller actin fold, structural protein, atp binding |
| Biological source | Bos taurus (bovine,cow,domestic cattle,domestic cow) More |
| Cellular location | Cytoplasm, cytoskeleton (By similarity): P61157 A7MB62 Q58CQ2 Q3MHR7 Q3T035 Q148J6 Q3SYX9 |
| Total number of polymer chains | 7 |
| Total formula weight | 224496.91 |
| Authors | Nolen, B.J.,Han, M. (deposition date: 2011-11-09, release date: 2013-02-13, Last modification date: 2024-02-28) |
| Primary citation | Baggett, A.W.,Cournia, Z.,Han, M.S.,Patargias, G.,Glass, A.C.,Liu, S.Y.,Nolen, B.J. Structural characterization and computer-aided optimization of a small-molecule inhibitor of the Arp2/3 complex, a key regulator of the actin cytoskeleton. Chemmedchem, 7:1286-1294, 2012 Cited by PubMed Abstract: 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. PubMed: 22623398DOI: 10.1002/cmdc.201200104 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.48 Å) |
Structure validation
Download full validation report
