A wealth of genetic information is available describing single-nucleotide variants in the human population that appear to be well-tolerated and in and of themselves do not confer disease. These variant data sets contain signatures about the protein structure-function relationships and provide an unbiased view of various protein functions in the context of human health. This information can be used to determine regional intolerance to variation, defined as the missense tolerance ratio (MTR), which is an indicator of stretches of the polypeptide chain that can tolerate changes without compromising protein function in a manner that impacts human health. This approach circumvents the lack of comprehensive data by averaging the data from adjacent residues on the polypeptide chain. We reasoned that many motifs in proteins consist of nonadjacent residues, but together function as a unit. We therefore developed an approach to analyze nearest neighbors in three-dimensional space as determined by crystallography rather than on the polypeptide chain. We used members of the GRIN gene family that encode subunits of NMDA-type ionotropic glutamate receptors (iGluRs) to exemplify the differences between these methods. Our method, 3DMTR, provides new information about regions of intolerance within iGluRs, allows consideration of protein–protein interfaces in multimeric proteins, and moves this important research tool from one-dimensional analysis to a structurally relevant tool. We validate the improved 3DMTR score by showing that it more accurately classifies the functional consequences of a set of newly measured and published point mutations of Grin family genes than existing methods.

中文翻译：

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三维错义容差率分析

有大量的遗传信息描述了人类中的单核苷酸变异，这些变异似乎具有良好的耐受性，并且其本身不会导致疾病。这些变异数据集包含有关蛋白质结构-功能关系的特征，并提供了人类健康背景下各种蛋白质功能的公正观点。该信息可用于确定区域对变异的不耐受性，定义为错义耐受率（MTR），它是多肽链延伸的指标，可以耐受变化而不以影响人类健康的方式损害蛋白质功能。这种方法通过对多肽链上相邻残基的数据进行平均来避免综合数据的缺乏。我们推断蛋白质中的许多基序由不相邻的残基组成，但作为一个单元一起发挥作用。因此，我们开发了一种方法来分析三维空间中由晶体学而不是多肽链确定的最近邻居。我们使用编码 NMDA 型离子型谷氨酸受体 (iGluR) 亚基的GRIN基因家族成员来举例说明这些方法之间的差异。我们的方法 3DMTR 提供了有关 iGluR 内不耐受区域的新信息，允许考虑多聚体蛋白质中的蛋白质-蛋白质界面，并将这一重要的研究工具从一维分析转移到结构相关的工具。我们通过证明改进的 3DMTR 评分比现有方法更准确地对一组新测量和发布的Grin家族基因点突变的功能后果进行分类来验证改进的 3DMTR 评分。