Understanding the structural and functional diversity of ATP-PPases using protein domains and functional families in...

ATP-pyrophosphatases (ATP-PPases) are the most primordial lineage of the large and diverse HUP (high-motif proteins, universal stress proteins, ATP-pyrophosphatase) superfamily. There are four different ATP-PPase substrate-specificity groups (SSGs), and members of each group show considerable sequence variation across the domains of life despite sharing the same catalytic function. Owing to the expansion in the number of ATP-PPase domain structures from advances in protein structure prediction by AlphaFold2 (AF2), we have characterized the two most populated ATP-PPase SSGs, the nicotinamide adenine dinucleotide synthases (NADSs) and guanosine monophosphate synthases (GMPSs). Local structural and sequence comparisons of NADS and GMPS identified taxonomic-group-specific functional motifs. As GMPS and NADS are potential drug targets of pathogenic microorganisms including Mycobacterium tuberculosis, bacterial GMPS and NADS specific functional motifs reported in this study, may contribute to antibacterial-drug development.