Small-molecule ligands of methyl-lysine binding proteins.
Small-molecule ligands of methyl-lysine binding proteins.
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DOI：
10.1021/jm200045v
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发表时间：
2011-04-14
影响因子：
7.3
通讯作者：
Frye, Stephen V.
中科院分区：
文献类型：
--
作者：
Herold, J. Martin;Wigle, Tim J.;Norris, Jacqueline L.;Lam, Robert;Korboukh, Victoria K.;Gao, Cen;Ingerman, Lindsey A.;Kireev, Dmitri B.;Senisterra, Guillermo;Vedadi, Masoud;Tripathy, Ashutosh;Brown, Peter J.;Arrowsmith, Cheryl H.;Jin, Jian;Janzen, William P.;Frye, Stephen V.
结合甲基化赖氨酸的蛋白质(组蛋白密码的“读取器”)是基因表达表观遗传调控的重要组成部分，也可以调节其他含有甲基赖氨酸的蛋白质，如p53和Rb。MBT结构域对甲基赖氨酸标记的识别导致染色质的紧致和转录状态的抑制。MBT结构域的拮抗剂将作为探针，询问这些蛋白质的功能作用，并作为靶类启动甲基赖氨酸阅读器的化学生物学。根据组蛋白多肽-MBT复合体的结构以及它们与MBT结构域的相互作用，用化学发光法和ITC法设计了小分子MBT拮抗剂。发现的配体拮抗天然的组蛋白多肽结合，与L3MBTL1的结合亲和力是其首选的组蛋白多肽的5倍。首次确定了与L3MBTL1结合的小分子的共晶结构，并为进一步的配体设计提供了新的结合要求。
Proteins which bind methylated lysines (“readers” of the histone code) are important components in the epigenetic regulation of gene expression and can also modulate other proteins that contain methyl-lysine such as p53 and Rb. Recognition of methyl-lysine marks by MBT domains leads to compaction of chromatin and a repressed transcriptional state. Antagonists of MBT domains would serve as probes to interrogate the functional role of these proteins and initiate the chemical biology of methyl-lysine readers as a target class. Small molecule MBT antagonists were designed based on the structure of histone peptide-MBT complexes and their interaction with MBT domains determined using a chemiluminescent assay and ITC. The ligands discovered antagonize native histone peptide binding, exhibiting 5-fold stronger binding affinity to L3MBTL1 than its preferred histone peptide. The first co-crystal structure of a small molecule bound to L3MBTL1 was determined and provides new insights into binding requirements for further ligand design.
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影响因子：
7.3
作者：
Kireev D;Wigle TJ;Norris-Drouin J;Herold JM;Janzen WP;Frye SV
通讯作者：
Frye SV
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
10.5
作者：
Berger, Shelley L.;Kouzarides, Tony;Shilatifard, Ali
通讯作者：
Shilatifard, Ali
影响因子：
8
作者：
Koga, H;Matsui, S;Saya, H
通讯作者：
Saya, H