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

2015; Nature Portfolio; Volume: 6; Issue: 1 Linguagem: Inglês

10.1038/ncomms7402

2041-1723

Pengfei Fang, Xue Yu, Seung Jae Jeong, Adam C. Mirando, Kaige Chen, Xin Chen, Sung‐Hoon Kim, Christopher S. Francklyn, Min Guo,

Genomics and Phylogenetic Studies

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.