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: Pengfei Fang, Xue Yu, Seung Jae Jeong, Adam Mirando, Kaige Chen, Xin Chen, Sunghoon Kim, Christopher S Francklyn, Min Guo
• Journal: Nature communications (Nat Commun) Vol. 6 Pg. 6402 (Mar 31 2015) ISSN: 2041-1723 [Electronic] England
• PMID: 25824639 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Escherichia coli Proteins
• Fatty Alcohols
• borrelidin
• Threonine-tRNA Ligase

Topics

• Amino Acid Sequence
• Binding Sites
• Catalytic Domain
• Crystallography, X-Ray
• Escherichia coli
• Escherichia coli Proteins (antagonists & inhibitors, metabolism)
• Fatty Alcohols (metabolism)
• Humans
• Organisms, Genetically Modified
• Threonine-tRNA Ligase (antagonists & inhibitors, genetics, metabolism)
• Transfer RNA Aminoacylation
• Yeasts (genetics)