最近对YAP -TEAD1复合物(51)(PDB登录号3KYS)的晶体结构的阐述开启了合理设计的直接YAP - TEAD相互作用抑制剂的可能性。晶体学表明YAP蛋白包裹在TEAD1 的YAP结合结构域周围,在三个不同的相互作用界面上形成广泛的相互作用。结构和突变研究鉴定了少量高度保守的氨基酸,即Ser 94,Phe 95和Phe 96,位于YAP的Ω环中,...
(B)YAP-TEAD(PDB代码3JUA,TEAD缺失,YAP为橙红色)和2:2 TAZ-TEAD复合体(PDB代码5GN0,TEAD为粉红色和紫色,TAZ为绿色和黄色)的叠加。 在一项致力于建立TEAD-YAP与TEAD-TAZ蛋白质-蛋白质相互作用之间的异同的大型研究中,通过SPR(表面等离子体共振)发现了类似的YAP片段(hYAP(61–99))具有相近的解离常数。(43)结...
当Hippo通路处于抑制状态时,YAP/TAZ去磷酸化后进入细胞核,通过 与转录因子TEADs相互作用诱导基因转录,从而导致肿瘤的发生。 [0004] TEAD(具有TEA/ATTS结构域的转录增强因子TEF)转录因子是Hippo信号通路的最 终效应器。哺乳动物TEAD蛋白家族包含四个成员,分别为TEAD1‑4,四种TEAD具有61%‑73% 的整体同源性。YAP...
YAP has an N-terminal TEAD-binding domain (TBD) followed by one or two WW domains and a C-terminal activation domain. (B) The crystal structure of the TEAD-YAP complex (PDB: 3KYS) reveals three interfaces between TEAD and YAP. TEAD YBD is colored green and YAP TBD magenta. TEAD YBD...
TEA结构域(TEAD)转录因子结合共激活剂YAP和TAZ并且调节Hippo信号通路的转录输出.TEAD蛋白质在调控器官大小和肿瘤形成过程中起着非常重要的作用.蛋白质的S型棕榈酰化修饰把一个脂肪酸盐—棕榈酸盐分子,附加到半胱氨酸残基上,并且调控着蛋白质的运输,膜定位和信号传输活动.基于不可逆的棕榈酰转移酶(PATs)的抑制剂来构...
a, Left, YAP and TAZ proteins mapped on the TEAD3 surface, as a result of structural alignments with the complex structures (PDB codes 5GN0, 5OAQ). The TEAD3 surface is shown in gray with the bound myristate in the buried LP drawn in dark gray. Middle/right, TEAD3–IAG933 cocrystal...
2.根据权利要求1所述的TEAD小分子抑制剂,其特征在于,可通过如下方式进行筛选, 包括如下步骤: 步骤一、受体准备:从PDB库中提取了PDB库号为7CNL的蛋白质晶体结构作为初始结构; 步骤二、虚拟筛选:以AutoGen为工具,进行潜在活性分子化合物自动生成; 步骤三、生物测试:在MolPort化合物分子数据库中寻找与AutoGen产生的潜在...
The recently reported crystal structure of TEAD4-TAZ complex (PDB Code 5GN0) in mouse reveals that the interactions between the two helices of YAP/TAZ and TEAD4 are highly conserved. Point mutation of the residue Tyr422 of TEAD4 protein would disrupt the relevant hydrogen bond and even ...
与TEAD2与1(PDB:5DQ8)络合物的结构相比,第一个2的苯环(TED-347)从Val-347的方向旋转大约90°,以形成共价键。第二个环和三氟甲基进一步移入疏水口袋中(图5A和5B)。然而,由于我们的多步浸泡实验以及由此产生的正密度,我们可以清楚地看到2(TED-347)在我们建议的Cys-380位置与TEAD2形成共价键。
Compound 6 is therefore the first inhibitor of YAP/TAZ-TEAD targeting interface 2. This molecule could serve with other pan-TEAD inhibitors such as interface 3 ligands, for the delineation of the relative importance of VGLL vs YAP/TAZ in a given cellular model. Graphical abstract Download: ...