3UKR

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

3UKR の概要

• エントリーDOI: 10.2210/pdb3ukr/pdb
• 関連するPDBエントリー: 3UKU 3ULE
• 分子名称: Actin-related protein 3, Actin-related protein 2, Actin-related protein 2/3 complex subunit 1B, ... (9 entities in total)
• 機能のキーワード: beta-propeller actin fold, structural protein, atp binding
• 由来する生物種: Bos taurus (bovine,cow,domestic cattle,domestic cow); 詳細
• 細胞内の位置: Cytoplasm, cytoskeleton (By similarity): P61157 A7MB62 Q58CQ2 Q3MHR7 Q3T035 Q148J6 Q3SYX9
• タンパク質・核酸の鎖数: 7
• 化学式量合計: 224496.91

構造登録者

Nolen, B.J.,Han, M. (登録日: 2011-11-09, 公開日: 2013-02-13, 最終更新日: 2024-02-28)

主引用文献

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

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: 22623398
DOI: 10.1002/cmdc.201200104

実験手法

X-RAY DIFFRACTION (2.48 Å)