Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase

Pengfei Fang, Xue Yu, Seung Jae Jeong, Adam Mirando, Kaige Chen, Xin Chen, Sunghoon Kim, Christopher S. Francklyn () and Min Guo ()
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Pengfei Fang: Scripps Research Institute, Scripps Florida
Xue Yu: Scripps Research Institute, Scripps Florida
Seung Jae Jeong: Medicinal Bioconvergence Research Center, Seoul National University
Adam Mirando: University of Vermont College of Medicine
Kaige Chen: Scripps Research Institute, Scripps Florida
Xin Chen: Scripps Research Institute, Scripps Florida
Sunghoon Kim: Medicinal Bioconvergence Research Center, Seoul National University
Christopher S. Francklyn: University of Vermont College of Medicine
Min Guo: Scripps Research Institute, Scripps Florida

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract The polyketide natural product borrelidin displays antibacterial, antifungal, antimalarial, anticancer, insecticidal and herbicidal activities through the selective inhibition of threonyl-tRNA synthetase (ThrRS). How borrelidin simultaneously attenuates bacterial growth and suppresses a variety of infections in plants and animals is not known. Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth ‘orthogonal’ subsite created as a consequence of binding. Thus, borrelidin competes with all three aminoacylation substrates, providing a potent and redundant mechanism to inhibit ThrRS during protein synthesis. These results highlight a surprising natural design to achieve the quadrivalent inhibition of translation through a highly conserved family of enzymes.

Date: 2015
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DOI: 10.1038/ncomms7402

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