The role of ZA channel water-mediated interactions in the design of bromodomain-selective BET inhibitors.
The role of ZA channel water-mediated interactions in the design of bromodomain-selective BET inhibitors.
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DOI：
10.1016/j.jmgm.2018.03.005
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发表时间：
2018-05
影响因子：
2.9
通讯作者：
Shelat AA
中科院分区：
文献类型：
--
作者：
Bharatham N;Slavish PJ;Shadrick WR;Young BM;Shelat AA
蛋白质的溴结构域和末端外结构域家族（BET）参与基因转录的调节，并且它们的失调与包括癌症在内的若干疾病有关。BET蛋白含有两个串联的溴结构域（BD 1和BD 2），其独立地识别乙酰化赖氨酸残基并且似乎具有不同的生物学作用。我们比较了几种已发表的共晶结构，并发现在BET溴结构域之间变化的底物结合口袋附近的五个位置。位于ZA回路中的一个位置具有独特的属性。在BRD 2 -4中，该残基在BD 1中为谷氨酰胺，在BD 2中为赖氨酸;在BRDT中，该残基在BD 1中为精氨酸，在BD 2中为天冬酰胺。使用分子建模，我们确定了溴结构域之间的水介导的网络在这个位置上的差异。分子动力学模拟有助于合理化所观察到的溴结构域的选择性的示例BET抑制剂和同源系列的四氢喹啉（THQ），不同的是一个单一的杂原子附近的ZA通道。2-呋喃SJ 830599，最BD 2-选择性THQ类似物，没有破坏水介导的网络中的任一个域，但静电排斥的特定安排的W5水偶极子在BD 1。我们的工作强调了探索水介导的相互作用来研究配体结合的价值，并强调了由于高去溶剂化惩罚而优化极性相互作用的困难。最后，我们建议对基于THQ的BET抑制剂进行进一步修饰，这将增加BRD 2 -4中的BD 2选择性，同时使对BRDT的一个或两个溴结构域的亲和力最小化。
The Bromodomain and Extra-Terminal domain family (BET) family of proteins are involved in the regulation of gene transcription, and their dysregulation is implicated in several diseases including cancer. BET proteins contain two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine residues and appear to have distinct biological roles. We compared several published co-crystal structures and found five positions near the substrate binding pocket that vary between BET bromodomains. One position located in the ZA loop has unique properties. In BRD2-4, this residue is glutamine in BD1 and lysine in BD2; in BRDT, this residue is arginine in BD1 and asparagine in BD2. Using molecular modeling, we identified differences in the water-mediated network at this position between bromodomains. Molecular dynamics simulations helped rationalize the observed bromodomain selectivity for exemplar BET inhibitors and a congeneric series of tetrahydroquinolines (THQ) that differed by a single heteroatom near the ZA channel. The 2-furan SJ830599, the most BD2-selective THQ analog, did not disrupt the water-mediated networks in either domain, but was electrostatically-repulsed by the specific arrangement of the W5 water dipole in BD1. Our work underscores the value of exploring water-mediated interactions to study ligand binding, and highlights the difficulty of optimizing polar interactions due to high desolvation penalties. Finally, we suggest further modifications to THQ-based BET inhibitors that would increase BD2-selectivity in BRD2-4, while minimizing affinity for one or both bromodomains of BRDT.
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影响因子：
14.8
作者：
Arrowsmith CH;Audia JE;Austin C;Baell J;Bennett J;Blagg J;Bountra C;Brennan PE;Brown PJ;Bunnage ME;Buser-Doepner C;Campbell RM;Carter AJ;Cohen P;Copeland RA;Cravatt B;Dahlin JL;Dhanak D;Edwards AM;Frederiksen M;Frye SV;Gray N;Grimshaw CE;Hepworth D;Howe T;Huber KV;Jin J;Knapp S;Kotz JD;Kruger RG;Lowe D;Mader MM;Marsden B;Mueller-Fahrnow A;Müller S;O'Hagan RC;Overington JP;Owen DR;Rosenberg SH;Roth B;Ross R;Schapira M;Schreiber SL;Shoichet B;Sundström M;Superti-Furga G;Taunton J;Toledo-Sherman L;Walpole C;Walters MA;Willson TM;Workman P;Young RN;Zuercher WJ
通讯作者：
Zuercher WJ
DOI：
10.1126/science.1249830
发表时间：
2014-10-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baud MGJ;Lin-Shiao E;Cardote T;Tallant C;Pschibul A;Chan KH;Zengerle M;Garcia JR;Kwan TT;Ferguson FM;Ciulli A
通讯作者：
Ciulli A
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.1
作者：
LAMBRAKOS, SG;BORIS, JP;NAGUMO, M
通讯作者：
NAGUMO, M
影响因子：
14.8
作者：
Ciceri, Pietro;Mueller, Susanne;Knapp, Stefan
通讯作者：
Knapp, Stefan