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 orthogonalsubsite 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.
Bibliographical noteFunding Information:
We thank Dr P. Schimmel, R.A. Copeland and L. Hedstrom for comments, Dr D.J. Slade for assistance in data collection. Use of the Advanced Photon Source and Advanced Light Source are supported by the US Department of Energy under Contract No. DE-AC02-06CH11357, DE-AC02-05CH11231. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the US Department of Energy under Contract No. DE-AC02-76SF00515 and by the National Institute of General Medical Sciences including P41GM103393. This work was supported by the Korean Global Frontier Project grant NRF-M1AXA002-2010-0029785 to S.K., grants from the National Institutes of Health NIEHS T32 ES007122-23 to A.M., GM54899 to C.S.F., GM100136 and GM106134 to M.G.
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All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)