Amphipathic small molecules mimic the binding mode and function of endogenous transcription factors.
Amphipathic small molecules mimic the binding mode and function of endogenous transcription factors.
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DOI：
10.1021/cb900028j
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发表时间：
2009-05-15
影响因子：
4
通讯作者：
Mapp, Anna K.
中科院分区：
文献类型：
--
作者：
Buhrlage, Sara J.;Bates, Caleb A.;Rowe, Steven P.;Minter, Aaron R.;Brennan, Brian B.;Majmudar, Chinmay Y.;Wemmer, David E.;Al-Hashimi, Hashim;Mapp, Anna K.
重组蛋白质结合模式的小分子，并在这样做时引发程序化的功能反应，在控制复杂的生物过程中提供了相当大的优势。然而，这些分子的开发挑战是巨大的。许多蛋白质-蛋白质相互作用需要在相对大的表面积上的多个接触点。更重要的是，几种结合模式可以叠加在蛋白质内的单个序列上，并且必须为这种多模式结合预先编程真正的小分子置换。这是转录激活因子的转录激活结构域或转录因子的情况，因为这些mofif利用表征不佳的多配偶体结合谱来刺激基因表达。在这里，我们描述了一类独特的小分子，表现出类似于天然转录激活结构域的功能和结合特征。特别值得注意的是，小分子是第一个被报道结合到CREB结合蛋白（CBP）内的KIX结构域的天然激活剂所利用的位点。此外，功能性和非功能性小分子的比较表明，与CBP的相互作用是转录活性的关键贡献者。总而言之，证据表明小分子TAD模拟了其天然对应物的功能和机制，从而为小分子转录开关的更广泛开发提供了框架。
Small molecules that reconstitute the binding mode(s) of a protein and in doing so elicit a programmed functional response offer considerable advantages in the control of complex biological processes. The development challenges of such molecules are significant, however. Many protein-protein interactions require multiple points of contact over relatively large surface areas. More significantly, several binding modes can be superimposed upon a single sequence within a protein, and a true small molecule replacement must be pre-programmed for such multi-modal binding. This is the case for the transcriptional activation domain or TAD of transcriptional activators as these mofifs utilize a poorly characterized multi-partner binding profile in order to stimulate gene expression. Here we describe a unique class of small molecules that exhibit both function and a binding profile analogous to natural transcriptional activation domains. Of particular note, the small molecules are the first reported to bind to the KIX domain within the CREB binding protein (CBP) at a site that is utilized by natural activators. Further, a comparison of functional and non-functional small molecules indicates that an interaction with CBP is a key contributor to transcriptional activity. Taken together, the evidence suggests that the small molecule TADs mimic both the function and mechanism of their natural counterparts and thus present a framework for the broader development of small molecule transcriptional switches.
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影响因子：
1.6
作者：
DelProposto, James;Majmudar, Chinmay Y.;Brown, William Clay
通讯作者：
Brown, William Clay
影响因子：
5.6
作者：
De Guzman, RN;Goto, NK;Wright, PE
通讯作者：
Wright, PE
影响因子：
3.5
作者：
Casey, Ryan J.;Desaulniers, Jean-Paul;Mapp, Anna K.
通讯作者：
Mapp, Anna K.
影响因子：
3.3
作者：
Chen, X;Cheung, ST;Brown, PO
通讯作者：
Brown, PO
DOI：
10.1073/pnas.202162199
发表时间：
2002-10-01
影响因子：
11.1
作者：
Asada, S;Choi, Y;Uesugi, M
通讯作者：
Uesugi, M