Druggable protein interaction sites are more predisposed to surface pocket formation than the rest of the protein surface.
Druggable protein interaction sites are more predisposed to surface pocket formation than the rest of the protein surface.
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DOI：
10.1371/journal.pcbi.1002951
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发表时间：
2013
影响因子：
4.3
通讯作者：
Karanicolas J
中科院分区：
文献类型：
--
作者：
Johnson DK;Karanicolas J
尽管通过高通量筛选引起了强烈的兴趣和相当大的努力，但直接抑制蛋白质-蛋白质相互作用的小分子的例子很少。这表明，许多蛋白质相互作用表面可能不是本质上的“药物”的小分子，并提升了重要性的几个成功的例子，作为模型系统，以提高我们的基本理解的药物。在这里，我们描述了一种方法，用于探索富含构象的蛋白质波动含有适合小分子结合的表面口袋。从一组七个未结合的蛋白质结构开始，我们发现，低能量口袋的构象的存在确实是一个签名的可药用蛋白质相互作用位点和类似的表面口袋上的蛋白质上的其他地方没有形成。我们进一步发现，这种有偏见的方法产生的构象合奏在结构上类似于已知的走廊结合的结构更接近于等价的合奏无偏见的构象。总的来说，这些结果表明，“药物性”是一种通过其形成口袋的倾向在蛋白质表面上编码的属性，并激发了一种模型，其中易感口袋的原始特征限制了互补配体的范围;额外的较小构象变化则响应于特定配体的细节。我们预计，这里描述的见解将证明在选择治疗干预的蛋白质靶点有用。鉴定蛋白质相互作用的小分子抑制剂传统上对现代筛选方法提出了挑战，尽管兴趣源于这样的相互作用包括细胞增殖、分化和存活的潜在机制的事实。这表明，许多蛋白质相互作用表面可能不是本质上的“药物”的小分子，并提升了重要性的几个成功的例子作为模型系统，以提高我们的理解的因素，药物。在这里，我们描述了一种新的方法来探索蛋白质的波动，导致适合小分子结合的表面口袋。我们发现，这种口袋的存在确实是一个可药物化的蛋白质相互作用位点的签名，这表明“药物化”是一种通过其形成口袋的倾向编码在蛋白质表面上的属性。我们预计，这里描述的见解将证明在选择治疗干预的蛋白质靶点有用。
Despite intense interest and considerable effort via high-throughput screening, there are few examples of small molecules that directly inhibit protein-protein interactions. This suggests that many protein interaction surfaces may not be intrinsically “druggable” by small molecules, and elevates in importance the few successful examples as model systems for improving our fundamental understanding of druggability. Here we describe an approach for exploring protein fluctuations enriched in conformations containing surface pockets suitable for small molecule binding. Starting from a set of seven unbound protein structures, we find that the presence of low-energy pocket-containing conformations is indeed a signature of druggable protein interaction sites and that analogous surface pockets are not formed elsewhere on the protein. We further find that ensembles of conformations generated with this biased approach structurally resemble known inhibitor-bound structures more closely than equivalent ensembles of unbiased conformations. Collectively these results suggest that “druggability” is a property encoded on a protein surface through its propensity to form pockets, and inspire a model in which the crude features of the predisposed pocket(s) restrict the range of complementary ligands; additional smaller conformational changes then respond to details of a particular ligand. We anticipate that the insights described here will prove useful in selecting protein targets for therapeutic intervention. Identifying small-molecule inhibitors of protein interactions has traditionally presented a challenge for modern screening methods, despite interest stemming from the fact that such interactions comprise the underlying mechanisms for cell proliferation, differentiation, and survival. This suggests that many protein interaction surfaces may not be intrinsically “druggable” by small molecules, and elevates in importance the few successful examples as model systems for improving our understanding of factors contributing to druggability. Here we describe a new approach for exploring protein fluctuations leading to surface pockets suitable for small molecule binding. We find that the presence of such pockets is indeed a signature of druggable protein interaction sites, suggesting that “druggability” is a property encoded on a protein surface through its propensity to form pockets. We anticipate that the insights described here will prove useful in selecting protein targets for therapeutic intervention.
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影响因子：
3
作者：
Landon, Melissa R.;Amaro, Rommie E.;Baron, Riccardo;Ngan, Chi Ho;Ozonoff, David;McCammon, J. Andrew;Vajda, Sandor
通讯作者：
Vajda, Sandor
影响因子：
7.3
作者：
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Helms, Volkhard
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通讯作者：
Schroeder M
影响因子：
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作者：
Laurie, ATR;Jackson, RM
通讯作者：
Jackson, RM
影响因子：
5.5
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Bahar, Ivet