Prediction of structure of human WNT-CRD (FZD) complex for computational drug repurposing.
Prediction of structure of human WNT-CRD (FZD) complex for computational drug repurposing.
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DOI：
10.1371/journal.pone.0054630
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kamal MA
中科院分区：
文献类型：
--
作者：
Ain QU;Seemab U;Rashid S;Nawaz MS;Kamal MA
观察到的各种细胞外和细胞内WNT（无翼，Int-1原癌基因）信号传导组分的遗传改变可导致基因表达的增加或减少，因此可被有效地阻断。这些遗传学靶点可能包括阻止WNT-FZD（Frizzled）结合、破坏β-catenin以及Axin、APC和GSK-3β复合物的形成。因此，这些相互作用伙伴的局部靶向可以帮助设计针对WNT信号传导的新型抑制剂。我们的研究是我们以前工作的延伸，我们提出了WNT基因簇（WNT-1，WNT-6，WNT-10A和WNT-10 B）在人乳腺癌中的共调控表达模式。我们在这里提出的计算建模的三维结构的人WNT-1的复杂的FZD-1 CRD（半胱氨酸丰富的结构域）受体。发现富含半胱氨酸的二聚体结构域适合WNT蛋白进化上保守的U形沟。U形裂缝的两端含有N-末端和C-末端疏水残基，从而为卷曲受体提供强疏水部分并充当WNT-FZD相互作用的最大结合口袋。对这个裂缝的详细结构分析显示，表面的最大原子距离为1.28纳米，在底部缩小到1.17纳米，再次增加到1.27纳米。总之，进行WNT蛋白的结构预测分析，以揭示有关翻译后修饰位点的新细节，并绘制有效WNT抑制剂的新型药效团模型。
The observed genetic alterations of various extracellular and intracellular WNT (Wingless, Int-1 proto-oncogene) signaling components can result in an increase or decrease in gene expression, and hence can be obstructed proficiently. These genetics target sites may include the prevention of WNT-FZD (Frizzled) binding, destruction of β-catenin and formation of Axin, APC and GSK-3β complex. Hence, the localized targeting of these interacting partners can help in devising novel inhibitors against WNT signaling. Our present study is an extension of our previous work, in which we proposed the co-regulated expression pattern of the WNT gene cluster (WNT-1, WNT-6, WNT-10A and WNT-10B) in human breast carcinoma. We present here the computationally modeled three dimensional structure of human WNT-1 in complex with the FZD-1 CRD (Cysteine Rich Domain) receptor. The dimeric cysteine-rich domain was found to fit into the evolutionarily conserved U-shaped groove of WNT protein. The two ends of the U- shaped cleft contain N-terminal and C-terminal hydrophobic residues, thus providing a strong hydrophobic moiety for the frizzled receptor and serving as the largest binding pocket for WNT-FZD interaction. Detailed structural analysis of this cleft revealed a maximum atomic distance of ∼28 Å at the surface, narrowing down to ∼17 Å and again increasing up to ∼27 Å at the bottom. Altogether, structural prediction analysis of WNT proteins was performed to reveal newer details about post-translational modification sites and to map the novel pharmacophore models for potent WNT inhibitors.
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影响因子：
1.9
作者：
Malinauskas, Tomas
通讯作者：
Malinauskas, Tomas
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：
14.9
作者：
Hubbard, T;Barker, D;Clamp, M
通讯作者：
Clamp, M
影响因子：
4
作者：
Carron, C;Pascal, A;Umbhauer, M
通讯作者：
Umbhauer, M
DOI：
10.1136/mp.55.4.220
发表时间：
2002-08-01
期刊：
JOURNAL OF CLINICAL PATHOLOGY-MOLECULAR PATHOLOGY
影响因子：
--
作者：
Holcombe, RF;Marsh, JL;Truong, T
通讯作者：
Truong, T