Exploring functional insights into the human gut microbiome via the structural proteome

The human gut microbiome contains numerous proteins whose functions remain elusive yet are pivotal to host health. Sequence-based methods often falter when attempting to infer functions within this microbial proteome due to evolutionary divergence. To address this challenge, we develop the Human Gut Microbial Protein Structure Database, which incorporates ∼2.7 million predicted protein structures. Our findings reveal that structural analogy enhances the annotation of phage proteins. We detail the structural diversification of phage endolysins and confirm their potential in eliminating gut pathobionts. Furthermore, our structure-guided approach is effective in the identification of microbial-host isozymes. By employing structural alignments, we identify previously unrecognized bacterial enzymes involved in melatonin biosynthesis. Finally, we present an alignment-free method, dense enzyme retrieval, based on structure-encoded protein language models for ultrafast and sensitive detection of remote homologs. Our research underscores the value of computational structural genomics in elucidating the functional landscape of the human gut microbiome.