Solution structure ensemble of human obesity-associated protein FTO reveals druggable surface pockets at the interface between the N- and C-terminal domain.
Solution structure ensemble of human obesity-associated protein FTO reveals druggable surface pockets at the interface between the N- and C-terminal domain.
复制标题
DOI：
10.1016/j.jbc.2022.101907
复制
发表时间：
2022-05
影响因子：
4.8
通讯作者：
Venditti, Vincenzo
中科院分区：
文献类型：
--
作者：
Khatiwada, Balabhadra;Nguyen, Trang T.;Purslow, Jeffrey A.;Venditti, Vincenzo
脂肪量和肥胖相关的FTO蛋白催化N6-甲基腺苷的去甲基化，N6-甲基腺苷是一种表观遗传标记，通过调节RNA分子的转录、翻译和细胞定位来控制几种代谢途径。自从发现FTO的过度表达与肥胖和癌症的发展有关以来，FTO一直是筛选活动和基于结构的药物设计工作的目标。尽管产生了几种FTO抑制剂，但这些抑制剂通常缺乏效力或选择性。在此，我们研究了人FTO在溶液中的结构和动力学。我们表明，催化N-末端结构域的结构是不稳定的，在没有C-末端结构域，这解释了为什么隔离的N-末端结构域是不称职的催化，并表明该域的相互作用代表了特定抑制剂的发展目标。然后，通过使用NMR弛豫测量，我们表明，FTO结构域，活性位点，和几个外围环之间的接口进行皮秒纳秒和微秒毫秒的时间尺度上的构象动力学。与此一致，我们发现，测量的骨架酰胺残留偶极耦合FTO在噬菌体PF 1是不一致的静态晶体结构的酶。最后，我们产生了一个构象合奏载脂蛋白FTO，满足解决方案NMR数据相结合的实验残留偶极耦合与加速分子动力学模拟。总之，在这项工作中报告的结构合奏提供了一个原子分辨率模型的载脂蛋白FTO和揭示瞬态表面口袋域界面，代表潜在的目标，设计变构抑制剂。
The fat mass and obesity-associated FTO protein catalyzes demethylation of the N6-methyladenosine, an epigenetic mark that controls several metabolic pathways by modulating the transcription, translation, and cellular localization of RNA molecules. Since the discovery that its overexpression links to the development of obesity and cancer, FTO was the target of screening campaigns and structure-based drug design efforts. Although several FTO inhibitors were generated, these often lack potency or selectivity. Herein, we investigate the structure and dynamics of human FTO in solution. We show that the structure of the catalytic N-terminal domain is unstable in the absence of the C-terminal domain, which explains why the isolated N-terminal domain is incompetent for catalysis and suggests that the domain interaction represents a target for the development of specific inhibitors. Then, by using NMR relaxation measurements, we show that the interface between the FTO structural domains, the active site, and several peripheral loops undergo conformational dynamics on both the picosecond–nanosecond and microsecond–millisecond timescales. Consistent with this, we found that the backbone amide residual dipolar couplings measured for FTO in phage pf1 are inconsistent with the static crystal structure of the enzyme. Finally, we generated a conformational ensemble for apo FTO that satisfies the solution NMR data by combining the experimental residual dipolar couplings with accelerated molecular dynamics simulations. Altogether, the structural ensemble reported in this work provides an atomic-resolution model of apo FTO and reveals transient surface pockets at the domain interface that represent potential targets for the design of allosteric inhibitors.
登录
查看更多内容
影响因子：
64.8
作者：
Han, Zhifu;Niu, Tianhui;Chai, Jijie
通讯作者：
Chai, Jijie
影响因子：
30.8
作者：
通讯作者：
--
急性髓性白血病中致癌 FTO 去甲基酶的小分子靶向
影响因子：
50.3
作者：
Huang, Yue;Su, Rui;Yang, Cai-Guang
通讯作者：
Yang, Cai-Guang
影响因子：
4.1
作者：
Das, Mohua;Yang, Tianming;Woon, Esther C. Y.
通讯作者：
Woon, Esther C. Y.
通过小鼠和人 FTO 对单链 DNA 和 RNA 中的 3-甲基胸腺嘧啶和 3-甲基尿嘧啶进行氧化去甲基化。
影响因子：
3.5
作者：
Jia, Guifang;Yang, Cai-Guang;Yang, Shangdong;Jian, Xing;Yi, Chengqi;Zhou, Zhiqiang;He, Chuan
通讯作者：
He, Chuan