4P3N

Structural Basis for Full-Spectrum Inhibition of Threonyl-tRNA Synthetase by Borrelidin 1

Summary for 4P3N

• Entry DOI: 10.2210/pdb4p3n/pdb
• Related: 4P3O 4P3P
• Descriptor: Threonine--tRNA ligase, cytoplasmic, (1R,2R)-2-[(2S,4E,6E,8R,9S,11R,13S,15S,16S)-7-cyano-8,16-dihydroxy-9,11,13,15-tetramethyl-18-oxooxacyclooctadeca-4,6-dien-2-yl]cyclopentanecarboxylic acid, ZINC ION, ... (4 entities in total)
• Functional Keywords: synthetase, inhibitor, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 196092.13

Authors

Fang, P.,Yu, X.,Chen, K.,Chen, X.,Guo, M. (deposition date: 2014-03-09, release date: 2015-03-11, Last modification date: 2023-12-27)

Primary citation

Fang, P.,Yu, X.,Jeong, S.J.,Mirando, A.,Chen, K.,Chen, X.,Kim, S.,Francklyn, C.S.,Guo, M.
Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase.
Nat Commun, 6:6402-6402, 2015

PubMed 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.

PubMed: 25824639
DOI: 10.1038/ncomms7402

Experimental method

X-RAY DIFFRACTION (2.6 Å)