4I9O

Crystal Structure of GACKIX L664C Tethered to 1-10

4I9O の概要

• エントリーDOI: 10.2210/pdb4i9o/pdb
• 分子名称: CREB-binding protein, 1-{4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxypiperidin-1-yl}-3-sulfanylpropan-1-one, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: kix domain, transcriptional coactivator, transferase
• 由来する生物種: Mus musculus (mouse)
• 細胞内の位置: Cytoplasm : P45481
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 12631.18

構造登録者

Wang, N.,Meagher, J.L.,Stuckey, J.A.,Mapp, A.K. (登録日: 2012-12-05, 公開日: 2013-03-06, 最終更新日: 2024-11-06)

主引用文献

Wang, N.,Majmudar, C.Y.,Pomerantz, W.C.,Gagnon, J.K.,Sadowsky, J.D.,Meagher, J.L.,Johnson, T.K.,Stuckey, J.A.,Brooks, C.L.,Wells, J.A.,Mapp, A.K.
Ordering a dynamic protein via a small-molecule stabilizer.
J.Am.Chem.Soc., 135:3363-3366, 2013

PubMed Abstract: Like many coactivators, the GACKIX domain of the master coactivator CBP/p300 recognizes transcriptional activators of diverse sequence composition via dynamic binding surfaces. The conformational dynamics of GACKIX that underlie its function also render it especially challenging for structural characterization. We have found that the ligand discovery strategy of Tethering is an effective method for identifying small-molecule fragments that stabilize the GACKIX domain, enabling for the first time the crystallographic characterization of this important motif. The 2.0 Å resolution structure of GACKIX complexed to a small molecule was further analyzed by molecular dynamics simulations, which revealed the importance of specific side-chain motions that remodel the activator binding site in order to accommodate binding partners of distinct sequence and size. More broadly, these results suggest that Tethering can be a powerful strategy for identifying small-molecule stabilizers of conformationally malleable proteins, thus facilitating their structural characterization and accelerating the discovery of small-molecule modulators.

PubMed: 23384013
DOI: 10.1021/ja3122334

実験手法

X-RAY DIFFRACTION (2 Å)