Once experimentally prohibitive, structural studies of individual missense variants in proteins are increasingly feasible, and can provide a new level of insight into human genetic disease. One example of this is the recently identified inborn error of metabolism known as phosphoglucomutase-1 (PGM1) deficiency. Just as different variants of a protein can produce different patient phenotypes, they may also produce distinct biochemical phenotypes, affecting properties such as catalytic activity, protein stability, or 3D structure/dynamics. Experimental studies of missense variants, and particularly structural characterization, can reveal details of the underlying biochemical pathomechanisms of missense variants. Here, we review four examples of enzyme dysfunction observed in disease-related variants of PGM1. These studies are based on 11 crystal structures of wild-type (WT) and mutant enzymes, and multiple biochemical assays. Lessons learned include the value of comparing mutant and WT structures, synergy between structural and biochemical studies, and the rich understanding of molecular pathomechanism provided by experimental characterization relative to the use of predictive algorithms. We further note functional insights into the WT enzyme that can be gained from the study of pathogenic variants.

一旦实验性禁止，对蛋白质中单个错义变体进行结构研究就变得越来越可行，并且可以提供对人类遗传疾病的新认识。这方面的一个例子是最近发现的先天性代谢错误，称为磷酸葡萄糖突变酶1（PGM1）缺乏症。正如蛋白质的不同变体可以产生不同的患者表型一样，它们也可能产生不同的生化表型，从而影响诸如催化活性，蛋白质稳定性或3D结构/动力学等性质。错义变体的实验研究，尤其是结构表征，可以揭示错义变体的潜在生化病理机制的细节。在这里，我们回顾在疾病相关的PGM1变体中观察到的酶功能异常的四个例子。这些研究基于野生型（WT）和突变酶的11种晶体结构，以及多种生化分析。获得的经验教训包括比较突变体和野生型结构的价值，结构和生化研究之间的协同作用，以及相对于预测算法的使用，实验表征提供的对分子病理机制的丰富理解。我们进一步注意到对WT酶的功能见解，可以从致病性变体的研究中获得。