Scientists now have access to millions of accurate three-dimensional (3D) models of protein structures. How do we leverage 3D structural models to learn about microbial functions encoded in metagenomes? Here, we review recent developments using protein structural features to mine metagenomes from diverse environments ranging from the human gut to soil and ocean viromes. We compare 3D protein structural methods to characterize antibiotic resistance phenotypes, nutrient cycling, and host–drug–microbe interactions. Broadly, we encourage the scientific community to look beyond global sequence and structure alignments by considering fine-grained descriptors such as distance to ligand, active site, and tertiary interactions between amino acid residues scaling to microbiomes. Finally, we highlight structure-inspired approaches to chart new areas of microbial protein-coding sequence space.

科学家现在可以获得数百万个精确的蛋白质结构三维 (3D) 模型。我们如何利用 3D 结构模型来了解宏基因组中编码的微生物功能？在这里，我们回顾了利用蛋白质结构特征从人类肠道到土壤和海洋病毒组等不同环境中挖掘宏基因组的最新进展。我们比较 3D 蛋白质结构方法来表征抗生素耐药性表型、营养循环和宿主-药物-微生物相互作用。从广义上讲，我们鼓励科学界通过考虑细粒度描述符（例如与配体的距离、活性位点以及缩放到微生物组的氨基酸残基之间的三级相互作用）来超越全局序列和结构比对。最后，我们重点介绍了受结构启发的方法来绘制微生物蛋白质编码序列空间的新领域。