Cryo-EM reveals E. coli TGT structure, overturning enzyme model
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Researchers at UC San Diego determined the first cryo-EM structure of E. coli tRNA-guanine transglycosylase (TGT), showing the enzyme binds two tRNAs simultaneously. The finding overturns the prevailing model of bacterial TGT function and may aid drug design against Shigella.
The Structure
The team led by Neal Devaraj used cryo-electron microscopy to visualize E. coli TGT at atomic resolution, a feat previously impossible due to crystallization difficulties. The structure reveals the enzyme engaging its tRNA substrate in a complex that includes two tRNA molecules, not one as long assumed. This is the first reported cryo-EM visualization of E. coli TGT.
Implications for Drug Design
E. coli TGT is nearly identical to the enzyme in Shigella, which causes shigellosis. The new structural framework allows researchers to design inhibitors targeting both tRNA binding sites, potentially increasing drug efficacy. TGT has been investigated as an antivirulence target for drug-resistant Shigella.
Research Publication
The study, authored by Alexander Harjung et al., was published in the Proceedings of the National Academy of Sciences. Devaraj noted that understanding the dual-tRNA binding enables design of RNA substrates that bind several times more tightly than previous versions. The work may also advance RNA chemical biology applications.
What's Next
The team plans to use the structural data to design and test TGT inhibitors in vitro. It remains unclear whether the dual-tRNA binding mechanism is conserved across other bacterial pathogens.
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Cryo-EM reveals E. coli TGT structure, overturning enzyme model
