Ordering a dynamic protein via a small-molecule stabilizer.
Ordering a dynamic protein via a small-molecule stabilizer.
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DOI：
10.1021/ja3122334
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发表时间：
2013-03-06
影响因子：
15
通讯作者：
Mapp, Anna K.
中科院分区：
文献类型：
--
作者：
Wang, Ningkun;Majmudar, Chinmay Y.;Pomerantz, William C.;Gagnon, Jessica K.;Sadowsky, Jack D.;Meagher, Jennifer L.;Johnson, Taylor K.;Stuckey, Jeanne A.;Brooks, Charles L., III;Wells, James A.;Mapp, Anna K.
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 find that the ligand discovery strategy of Tethering is an effective method for identifying small molecule fragments that stabilize the GACKIX domain and enables, 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, revealing 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.
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影响因子：
3.5
作者：
Arai M;Dyson HJ;Wright PE
通讯作者：
Wright PE
影响因子：
4
作者：
Thompson, Andrea D.;Dugan, Amanda;Gestwicki, Jason E.;Mapp, Anna K.
通讯作者：
Mapp, Anna K.
影响因子：
6.8
作者：
Dunker, A. Keith;Silman, Israel;Sussman, Joel L.
通讯作者：
Sussman, Joel L.
DOI：
10.1002/anie.201206815
发表时间：
2012-11-05
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Majmudar CY;Højfeldt JW;Arevang CJ;Pomerantz WC;Gagnon JK;Schultz PJ;Cesa LC;Doss CH;Rowe SP;Vásquez V;Tamayo-Castillo G;Cierpicki T;Brooks CL 3rd;Sherman DH;Mapp AK
通讯作者：
Mapp AK
影响因子：
48
作者：
Park, CW;Marqusee, S
通讯作者：
Marqusee, S