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

Jialin Yin; Vaishali P Waman; Neeladri Sen; Mohd Firdaus-Raih; Su Datt Lam; Christine Orengo

doi:10.1016/j.str.2024.12.016

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

Structure. 2025 Jan 15:S0969-2126(24)00551-3. doi: 10.1016/j.str.2024.12.016. Online ahead of print.

Authors

Jialin Yin¹, Vaishali P Waman¹, Neeladri Sen¹, Mohd Firdaus-Raih², Su Datt Lam³, Christine Orengo⁴

Affiliations

¹ Department of Structural and Molecular Biology, University College London, London, UK.
² Department of Applied Physics, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Malaysia.
³ Department of Structural and Molecular Biology, University College London, London, UK; Department of Applied Physics, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Malaysia.
⁴ Department of Structural and Molecular Biology, University College London, London, UK. Electronic address: c.orengo@ucl.ac.uk.

PMID: 39826548
DOI: 10.1016/j.str.2024.12.016

Abstract

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.

Keywords: ATP-pyrophosphatase; CATH database; GMP synthase; HUP domain; NAD synthase; local structural comparison; protein superfamily; structural motifs; substrate specificities.