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首页> 外文期刊>Current medicinal chemistry >Improving the understanding of human genetic diseases through predictions of protein structures and protein-protein interaction sites.
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Improving the understanding of human genetic diseases through predictions of protein structures and protein-protein interaction sites.

机译：通过预测蛋白质结构和蛋白质-蛋白质相互作用位点，增进对人类遗传疾病的了解。

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Over 1,500 human disease genes have been identified, of which only a small fraction have experimental structural information on the protein products. To better understand the mechanisms of these hereditary diseases, we undertook a systematic study to predict the structures of disease proteins and characterize their interactions with other proteins. This study was facilitated by two tools developed previously: COBLATH, a structure-prediction method that exploits the complementarity of PSI-Blast and sequence-structure threading and PPISP, a method that predicts the residues involved in protein-protein interactions. In this initial study of human disease proteins, we were able to build structural models for 60 proteins involved in human diseases. For a number of proteins, new structural domains were identified. In the case of ABCD1, a protein responsible for adrenoleukodystrophy, the disease mutation P484R was positioned at the homodimer interface. This positioning is consistent with experimental observation that the P484R mutation impairs ABCD1 self-interaction and suggests that that the disease mechanism of this mutation lies in the impaired ABCD1 dimerization. This initial study illustrates the value of the predicted structure models and may serve as an example for expanded studies of other disease proteins.
机译：已经鉴定出超过1,500种人类疾病基因，其中只有一小部分具有有关蛋白质产物的实验结构信息。为了更好地了解这些遗传性疾病的机制，我们进行了系统的研究，以预测疾病蛋白的结构并表征其与其他蛋白的相互作用。先前开发的两种工具促进了这项研究：COBLATH，一种利用PSI-Blast和序列结构穿线的互补性的结构预测方法，以及PPISP，一种预测参与蛋白质-蛋白质相互作用的残基的方法。在人类疾病蛋白质的初步研究中，我们能够建立涉及人类疾病的60种蛋白质的结构模型。对于许多蛋白质，鉴定了新的结构域。对于负责肾上腺白质营养不良的蛋白质ABCD1，疾病突变P484R位于同源二聚体界面。此定位与P484R突变会损害ABCD1自相互作用的实验观察结果一致，并表明该突变的疾病机制在于受损的ABCD1二聚化。这项初步研究说明了预测的结构模型的价值，并可以作为其他疾病蛋白质的扩展研究的实例。

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