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

Fang, Pengfei; Yu, Xue; Jeong, Seung Jae; Mirando, Adam; Chen, Kaige; Chen, Xin; Kim, Sunghoon; Francklyn, Christopher S.; Guo, Min

doi:10.1038/ncomms7402

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

Journal Article · Tue Mar 31 00:00:00 EDT 2015 · Nature Communications

DOI:https://doi.org/10.1038/ncomms7402· OSTI ID:1259897

Fang, Pengfei ^[1]; Yu, Xue ^[1]; Jeong, Seung Jae ^[2]; Mirando, Adam ^[3]; Chen, Kaige ^[1]; Chen, Xin ^[1]; Kim, Sunghoon ^[2]; Francklyn, Christopher S. ^[3]; Guo, Min ^[1]

Scripps Research Inst., Jupiter, FL (United States)
Seoul National Univ. (Korea)
Univ. of Vermont College of Medicine, Burlington, VT (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE; National Inst. of General Medical Sciences; Korean Global Frontier Project; National Inst. of Health

Grant/Contract Number:: AC02-06CH11357; AC02-05CH11231; AC02-76SF00515; P41GM103393; M1AXA002-2010-0029785; T32 ES007122-23; GM54899; GM100136; GM106134

OSTI ID:: 1259897

Journal Information:: Nature Communications, Vol. 6, Issue 2015; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 54 works

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