A comprehensive survey of small-molecule binding pockets in proteins.
A comprehensive survey of small-molecule binding pockets in proteins.
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DOI：
10.1371/journal.pcbi.1003302
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发表时间：
2013-10
影响因子：
4.3
通讯作者：
Skolnick J
中科院分区：
文献类型：
--
作者：
Gao M;Skolnick J
许多生物活性来源于小分子配体与其蛋白质靶标之间的相互作用。这些相互作用的详细结构和物理化学表征可以显着加深我们对蛋白质功能的理解，并促进药物设计。在这里，我们提出了一个非冗余的约20,000个已知的配体结合位点，或口袋，蛋白质的大规模研究。我们发现蛋白质口袋的结构空间是拥挤的，可能是完整的，并且可以由大约1，000个口袋形状表示。相应地，近年来蛋白质数据库中储存的新口袋的增长率一直在稳步下降。此外，许多蛋白质口袋是混杂的，并与不同支架的配体相互作用。相反，许多配体是混杂的，并与结构上不同的口袋相互作用。通过物理化学和结构分析，我们提供了深入了解口袋混杂和配体混杂。最后，我们讨论了我们的研究预测的蛋白质-配体相互作用的口袋比较的基础上的影响。活细胞的生命依赖于许多不同的蛋白质来执行它们的功能。这些功能中的大多数植根于蛋白质和代谢物之间的相互作用，代谢物是生命所必需的小分子。通过靶向与疾病相关的特定蛋白质，药物分子可以提供治疗。通过分析蛋白质和小分子（或配体）的结构，深入了解它们之间相互作用的本质，可能有助于预测蛋白质功能或改进药物设计。在这方面的贡献，我们提出了一个大规模的分析，一个非冗余的一套超过20,000个实验蛋白质-配体复合物的结构，在目前的蛋白质数据库。我们寻求几个基本问题的答案：有多少代表性的口袋是作为蛋白质中的配体结合位点？通过匹配蛋白质口袋的结构，我们可以在多大程度上推断出类似的蛋白质-配体相互作用？在同一个口袋里发现的配体有多大不同？对于一个混杂的蛋白质口袋，一个口袋如何与非常不同的配体保持有利的相互作用？相反，与相同配体相互作用的口袋有多大不同？我们发现蛋白质口袋的结构空间很小，蛋白质混杂和配体混杂在自然界中都很常见。
Many biological activities originate from interactions between small-molecule ligands and their protein targets. A detailed structural and physico-chemical characterization of these interactions could significantly deepen our understanding of protein function and facilitate drug design. Here, we present a large-scale study on a non-redundant set of about 20,000 known ligand-binding sites, or pockets, of proteins. We find that the structural space of protein pockets is crowded, likely complete, and may be represented by about 1,000 pocket shapes. Correspondingly, the growth rate of novel pockets deposited in the Protein Data Bank has been decreasing steadily over the recent years. Moreover, many protein pockets are promiscuous and interact with ligands of diverse scaffolds. Conversely, many ligands are promiscuous and interact with structurally different pockets. Through a physico-chemical and structural analysis, we provide insights into understanding both pocket promiscuity and ligand promiscuity. Finally, we discuss the implications of our study for the prediction of protein-ligand interactions based on pocket comparison. The life of a living cell relies on many distinct proteins to carry out their functions. Most of these functions are rooted in interactions between the proteins and metabolites, small-molecules essential for life. By targeting specific proteins relevant to a disease, drug molecules may provide a cure. A deep understanding of the nature of interactions between proteins and small-molecules (or ligands) through analyzing their structures may help predict protein function or improve drug design. In this contribution, we present a large-scale analysis of a non-redundant set of over 20,000 experimental protein-ligand complex structures available in the current Protein Data Bank. We seek answers to several fundamental questions: How many representative pockets are there that serve as ligand-binding sites in proteins? To what extent can we infer a similar protein-ligand interaction by matching the structures of protein pockets? How different are the ligands found in the same pocket? For a promiscuous protein pocket, how does a pocket maintain favorable interactions with very different ligands? Conversely, how different are those pockets that interact with the same ligand? We find the structural space of protein pocket is small and that both protein promiscuity and ligand promiscuity are very common in Nature.
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影响因子：
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通讯作者：
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