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腾讯登录Nat Chem Biol：科学家发现细胞凋亡通路激活新机制
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<div> 本月出版的《自然—化学生物学》<em>Nature Chemical Biology</em>报道了一种通过新机制激活细胞凋亡通路的化合物。</div>
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<div> 本月出版的《自然—化学生物学》<em>Nature Chemical Biology</em>报道了一种通过新机制激活细胞凋亡通路的化合物。</div>
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由BcL-2蛋白家族所构成的复杂蛋白间互作网络既能抑制也能促使细胞凋亡的发生——这取决于其中各种不同蛋白的激活状态。在癌细胞群中，各种蛋白构成的激活平衡被打破，从而促使癌细胞存活。因而针对该蛋白家族的一些抗癌研究很大程度上着眼于抑制其中那些会促进细胞存活的蛋白活动。研究发现，其中一种被称为Bax的蛋白就足够具有激活细胞凋亡通路的能力。
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Loren Walensky等人发现，一种名为BAM7的小分子可以通过触发Bax蛋白中的构象变化，有选择地激活细胞，促使细胞凋亡。因为正常细胞和癌细胞都能表达Bax，所以该发现能否有效应用于抗癌治疗，还需要进一步的研究，但BAM7的发现以及其作为Bax的选择性激活物这一特点，意味着一种杀死癌细胞的新方法的诞生。
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<img src="http://www.bioon.com/biology/UploadFiles/201206/2012060609494253.jpg" alt="" width="113" height="149" border="0" />
<a title="" href="http://dx.doi.org/doi:10.1038/nchembio.995" target="_blank">doi:10.1038/nchembio.995</a>
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<br/><strong>Direct and selective small-molecule activation of proapoptotic BAX</strong><br/>
Evripidis Gavathiotis, Denis E Reyna, Joseph A Bellairs, Elizaveta S Leshchiner & Loren D Walensky
BCL-2 family proteins are key regulators of the apoptotic pathway. Antiapoptotic members sequester the BCL-2 homology 3 (BH3) death domains of proapoptotic members such as BAX to maintain cell survival. The antiapoptotic BH3-binding groove has been successfully targeted to reactivate apoptosis in cancer. We recently identified a geographically distinct BH3-binding groove that mediates direct BAX activation, suggesting a new strategy for inducing apoptosis by flipping BAX's 'on switch'. Here we applied computational screening to identify a BAX activator molecule that directly and selectively activates BAX. We demonstrate by NMR and biochemical analyses that the molecule engages the BAX trigger site and promotes the functional oligomerization of BAX. The molecule does not interact with the BH3-binding pocket of antiapoptotic proteins or proapoptotic BAK and induces cell death in a BAX-dependent fashion. To our knowledge, we report the first gain-of-function molecular modulator of a BCL-2 family protein and demonstrate a new paradigm for pharmacologic induction of apoptosis.
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<div><br/>来源：中国科学报</div>
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<div> 本月出版的《自然—化学生物学》<em>Nature Chemical Biology</em>报道了一种通过新机制激活细胞凋亡通路的化合物。</div>
</div>
<div id="region-column1and2-layout2">
由BcL-2蛋白家族所构成的复杂蛋白间互作网络既能抑制也能促使细胞凋亡的发生——这取决于其中各种不同蛋白的激活状态。在癌细胞群中，各种蛋白构成的激活平衡被打破，从而促使癌细胞存活。因而针对该蛋白家族的一些抗癌研究很大程度上着眼于抑制其中那些会促进细胞存活的蛋白活动。研究发现，其中一种被称为Bax的蛋白就足够具有激活细胞凋亡通路的能力。
<!--more-->
Loren Walensky等人发现，一种名为BAM7的小分子可以通过触发Bax蛋白中的构象变化，有选择地激活细胞，促使细胞凋亡。因为正常细胞和癌细胞都能表达Bax，所以该发现能否有效应用于抗癌治疗，还需要进一步的研究，但BAM7的发现以及其作为Bax的选择性激活物这一特点，意味着一种杀死癌细胞的新方法的诞生。
<div id="ztload">
<div>
<div>
<img src="http://www.bioon.com/biology/UploadFiles/201206/2012060609494253.jpg" alt="" width="113" height="149" border="0" />
<a title="" href="http://dx.doi.org/doi:10.1038/nchembio.995" target="_blank">doi:10.1038/nchembio.995</a>
PMC:
PMID:
</div>
<div>
<br/><strong>Direct and selective small-molecule activation of proapoptotic BAX</strong><br/>
Evripidis Gavathiotis, Denis E Reyna, Joseph A Bellairs, Elizaveta S Leshchiner & Loren D Walensky
BCL-2 family proteins are key regulators of the apoptotic pathway. Antiapoptotic members sequester the BCL-2 homology 3 (BH3) death domains of proapoptotic members such as BAX to maintain cell survival. The antiapoptotic BH3-binding groove has been successfully targeted to reactivate apoptosis in cancer. We recently identified a geographically distinct BH3-binding groove that mediates direct BAX activation, suggesting a new strategy for inducing apoptosis by flipping BAX's 'on switch'. Here we applied computational screening to identify a BAX activator molecule that directly and selectively activates BAX. We demonstrate by NMR and biochemical analyses that the molecule engages the BAX trigger site and promotes the functional oligomerization of BAX. The molecule does not interact with the BH3-binding pocket of antiapoptotic proteins or proapoptotic BAK and induces cell death in a BAX-dependent fashion. To our knowledge, we report the first gain-of-function molecular modulator of a BCL-2 family protein and demonstrate a new paradigm for pharmacologic induction of apoptosis.
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<div><br/>来源：中国科学报</div>
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