Structure-guided metagenome mining to tap microbial functional diversity

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.