Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase
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.
- Authors:
-
- Scripps Research Inst., Jupiter, FL (United States)
- Seoul National Univ. (Korea)
- Univ. of Vermont College of Medicine, Burlington, VT (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE; National Inst. of General Medical Sciences; Korean Global Frontier Project; National Inst. of Health
- OSTI Identifier:
- 1259897
- Grant/Contract Number:
- AC02-06CH11357; AC02-05CH11231; AC02-76SF00515; P41GM103393; M1AXA002-2010-0029785; T32 ES007122-23; GM54899; GM100136; GM106134
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 6; Journal Issue: 2015; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Biosynthesis; Natural products; Structural biology; tRNAs
Citation Formats
Fang, Pengfei, Yu, Xue, Jeong, Seung Jae, Mirando, Adam, Chen, Kaige, Chen, Xin, Kim, Sunghoon, Francklyn, Christopher S., and Guo, Min. Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase. United States: N. p., 2015.
Web. doi:10.1038/ncomms7402.
Fang, Pengfei, Yu, Xue, Jeong, Seung Jae, Mirando, Adam, Chen, Kaige, Chen, Xin, Kim, Sunghoon, Francklyn, Christopher S., & Guo, Min. Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase. United States. https://doi.org/10.1038/ncomms7402
Fang, Pengfei, Yu, Xue, Jeong, Seung Jae, Mirando, Adam, Chen, Kaige, Chen, Xin, Kim, Sunghoon, Francklyn, Christopher S., and Guo, Min. Tue .
"Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase". United States. https://doi.org/10.1038/ncomms7402. https://www.osti.gov/servlets/purl/1259897.
@article{osti_1259897,
title = {Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase},
author = {Fang, Pengfei and Yu, Xue and Jeong, Seung Jae and Mirando, Adam and Chen, Kaige and Chen, Xin and Kim, Sunghoon and Francklyn, Christopher S. and Guo, Min},
abstractNote = {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.},
doi = {10.1038/ncomms7402},
journal = {Nature Communications},
number = 2015,
volume = 6,
place = {United States},
year = {Tue Mar 31 00:00:00 EDT 2015},
month = {Tue Mar 31 00:00:00 EDT 2015}
}
Web of Science
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