8POS

Crystal structure of wolbachia leucyl-tRNA synthetase editing domain bound to cmpd9-AMP adduct

Summary for 8POS

• Entry DOI: 10.2210/pdb8pos/pdb
• Related: 8POQ 8POR
• Descriptor: Leucine--tRNA ligase, [(1R,3'S,5S,6R,8R)-3'-(aminomethyl)-8-(6-aminopurin-9-yl)-4'-bromanyl-7'-[3-[methyl-(phenylmethyl)amino]propoxy]spiro[2,4,7-trioxa-3$l^{4}-borabicyclo[3.3.0]octane-3,1'-3H-2,1$l^{4}-benzoxaborole]-6-yl]methyl dihydrogen phosphate, SULFATE ION, ... (4 entities in total)
• Functional Keywords: leucine trna ligase, atp binding protein, trna aminoacylation for protein translation, cytosolic reaction catalysed: atp + l-leucine + trna(leu) = amp + diphosphate + l-leucyl-trna(leu), ligase
• Biological source: Wolbachia endosymbiont strain TRS of Brugia malayi
• Total number of polymer chains: 2
• Total formula weight: 41647.00

Authors

Palencia, A.,Hoffmann, G. (deposition date: 2023-07-05, release date: 2024-06-12, Last modification date: 2024-07-24)

Primary citation

Hoffmann, G.,Lukarska, M.,Clare, R.H.,Masters, E.K.G.,Johnston, K.L.,Ford, L.,Turner, J.D.,Ward, S.A.,Taylor, M.J.,Jensen, M.R.,Palencia, A.
Targeting a microbiota Wolbachian aminoacyl-tRNA synthetase to block its pathogenic host.
Sci Adv, 10:eado1453-eado1453, 2024

PubMed Abstract: The interplay between humans and their microbiome is crucial for various physiological processes, including nutrient absorption, immune defense, and maintaining homeostasis. Microbiome alterations can directly contribute to diseases or heighten their likelihood. This relationship extends beyond humans; microbiota play vital roles in other organisms, including eukaryotic pathogens causing severe diseases. Notably, , a bacterial microbiota, is essential for parasitic worms responsible for lymphatic filariasis and onchocerciasis, devastating human illnesses. Given the lack of rapid cures for these infections and the limitations of current treatments, new drugs are imperative. Here, we disrupt 's symbiosis with pathogens using boron-based compounds targeting an unprecedented enzyme, leucyl-tRNA synthetase (LeuRS), effectively inhibiting its growth. Through a compound demonstrating anti- efficacy in infected cells, we use biophysical experiments and x-ray crystallography to elucidate the mechanism behind LeuRS inhibition. We reveal that these compounds form adenosine-based adducts inhibiting protein synthesis. Overall, our study underscores the potential of disrupting key microbiota to control infections.

PubMed: 38985862
DOI: 10.1126/sciadv.ado1453

Experimental method

X-RAY DIFFRACTION (2.137 Å)