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TitleSelective inhibition of Mycobacterium tuberculosis GpsI unveils a novel strategy to target the RNA metabolism.
Journal, issue, pagesNucleic Acids Res, Vol. 53, Issue 11, Year 2025
Publish dateJun 6, 2025
AuthorsTizian Griesser / Rui Wang / Irene Pachon Angona / Janis Rogenmoser / Julia Obrist / Gisbert Schneider / Peter Sander /
PubMed AbstractPolyribonucleotide nucleotidyl-transferases (PNPases) play a critical role in the degradation of mRNA. The mycobacterial PNPase, guanosine penta-phosphate synthase I (GpsI), is an essential enzyme ...Polyribonucleotide nucleotidyl-transferases (PNPases) play a critical role in the degradation of mRNA. The mycobacterial PNPase, guanosine penta-phosphate synthase I (GpsI), is an essential enzyme in Mycobacterium tuberculosis (Mtb), collaborating with endoribonucleases and helicases to process RNA. In this study, we identify GpsI as a novel and underexplored drug target. The inhibitor 1-(4'-(2-phenyl-5-(trifluoromethyl) oxazole-4-carboxamido)-[1,1'-biphenyl]-4-caroxamido) cyclopentane-1-carboxylic acid (X1), discovered through a whole-cell screening, specifically inhibits GpsI activity in biochemical assays. Biochemical and physiological analyses of engineered GpsI variants and recombinant Mycobacterium smegmatis pinpoint amino acids 328 and 527 as critical residues for the selective activity of X1 against Mtb complex. High-resolution cryo-electron microscopy analysis of the ternary GpsI-X1-poly(A) complex elucidates the drug-binding pocket, providing insight into its mechanism of action. This study introduces a potent inhibitor targeting the underexplored Mtb-GpsI and offers a molecular explanation for its selective specificity.
External linksNucleic Acids Res / PubMed:40530695 / PubMed Central
MethodsEM (single particle)
Resolution1.93 - 1.98 Å
Structure data

51454

9gms

EMDB-51454, PDB-9gms:
Mtb PNPase Rv2783c
Method: EM (single particle) / Resolution: 1.98 Å

51455

9gmt

EMDB-51455, PDB-9gmt:
Mtb PNPase Rv2783c Mutant L328F
Method: EM (single particle) / Resolution: 1.93 Å

Chemicals

PDB-1im2:
HslU, Haemophilus Influenzae, Selenomethionine Variant

Source
  • mycobacterium tuberculosis (bacteria)
KeywordsRNA / PNPase / GpsI / RNA Degradosome / PNPase Inhibitor

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