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Single nucleotide variation catalogue from clinical isolates mapped on tertiary and quaternary structures of ESX-1 related proteins reveals critical regions as putative Mtb therapeutic targets

O Tzfadia(1,5) A Siroy(2) A Vujkovic(1,5) J Snobre(1,6) A Gijsbers(2) R Vargas(4) W Mulders(1) C Meehan(1,3) M Farhat(4) P Peters(2) B C de Jong(1,5) R Ravelli()

1:Institute for Tropical Medicine; 2:Maastricht University; 3:Nottingham Trent University; 4:Harvard Medical School; 5:University of Antwerp; 6:Vrije Universiteit Brussel (VUB)

Proteins encoded by the ESX-1 related genes are essential for full virulence in all Mycobacterium tuberculosis complex (MTBc) lineages, the pathogens with the highest mortality worldwide. Identifying critical regions in these ESX-1 related proteins could provide preventive or therapeutic targets for MTB infection, the game changer needed for tuberculosis control. We analysed a compendium of clinical MTB isolates from all lineages from >32,000 patients and identified single nucleotide variations (SNV) in ESX-1 genes. When mutations were mapped on the surface of known and alphafold-predicted ternary protein structures, fully conserved regions emerged which sat at the interface of known quaternary structures or could be predicted to be involved in yet-to-be-discovered interactions. Some clonal prevalent mutants circulated (found in >1% of the isolates): these were mostly located at the surface of globular domains, remote from known intra- and inter-molecular protein–protein interactions. Fully conserved intrinsically disordered regions (IDRs) of proteins were found, suggesting that these are crucial for the pathogenicity of the MTB. Altogether, our findings provide an evolutionary structural perspective on MTB virulence and highlight hyper conserved regions of proteins as attractive vaccine antigens and drug targets. Extending this approach to all MTB genes and other pathogens can provide a novel critical resource for the development of innovative tools for pathogen control.

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