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PDBsum entry 4p3n
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Ligase/ligase inhibitor
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PDB id
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4p3n
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PDB id:
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| Name: |
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Ligase/ligase inhibitor
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Title:
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Structural basis for full-spectrum inhibition of threonyl-tRNA synthetase by borrelidin 1
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Structure:
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Threonine--tRNA ligase, cytoplasmic. Chain: a, b, c, d. Fragment: unp residues 322-723. Synonym: threonyl-tRNA synthetase, thrrs. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: tars. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.60Å
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R-factor:
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0.229
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R-free:
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0.255
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Authors:
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P.Fang,X.Yu,K.Chen,X.Chen,M.Guo
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Key ref:
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P.Fang
et al.
(2015).
Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase.
Nat Commun,
6,
6402.
PubMed id:
DOI:
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Date:
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09-Mar-14
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Release date:
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11-Mar-15
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PROCHECK
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Headers
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References
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P26639
(SYTC_HUMAN) -
Threonine--tRNA ligase 1, cytoplasmic from Homo sapiens
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Seq:
Struc:
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723 a.a.
402 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.6.1.1.3
- threonine--tRNA ligase.
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Reaction:
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tRNA(Thr) + L-threonine + ATP = L-threonyl-tRNA(Thr) + AMP + diphosphate + H+
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tRNA(Thr)
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L-threonine
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+
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ATP
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=
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L-threonyl-tRNA(Thr)
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+
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AMP
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+
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diphosphate
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Nat Commun
6:6402
(2015)
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PubMed id:
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Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase.
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P.Fang,
X.Yu,
S.J.Jeong,
A.Mirando,
K.Chen,
X.Chen,
S.Kim,
C.S.Francklyn,
M.Guo.
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ABSTRACT
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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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