AI-first structural identification of pathogenic protein target interfaces.

The risk of pandemics is increasing as global population growth and interconnectedness accelerate. Understanding the structural basis of protein-protein interactions between pathogens and hosts is critical for elucidating pathogenic mechanisms and guiding treatment or vaccine development. Despite 21,064 experimentally supported human-pathogen interactions in the HPIDB, only 52 have resolved structures in the PDB, representing just 0.2%. Advances in protein complex structure prediction, such as AlphaFold, now enable highly accurate modelling of heterodimeric complexes, though their application to host-pathogen interactions, which have distinct evolutionary dynamics, remains underexplored. Here, we investigate the structural protein-protein interaction network between humans and ten pathogens, predicting structures for 9,452 interactions, only 10 of which have known structures. We identify 30 interactions with an expected TM-score ≥0.9, tripling the structural coverage in these networks. A detailed analysis of the Francisella tularensis dihydroprolyl dehydrogenase (IPD) complex with human immunoglobulin kappa constant (IGKC) using homology modelling and native mass spectrometry confirms a predicted 1:2:1 heterotetramer, suggesting potential roles in immune evasion. These findings highlight the transformative potential of structure prediction for rapidly advancing vaccine and drug development against novel pathogenic targets.