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PDBsum entry 2v0c
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Ligase PDB id
2v0c

 

 

 

 

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Contents
Protein chain
810 a.a. *
Ligands
LEU-LMS
ANZ
SO4 ×5
Metals
_ZN ×2
Waters ×684
* Residue conservation analysis
PDB id:
2v0c
Name: Ligase
Title: Leucyl-tRNA synthetase from thermus thermophilus complexed with a sulphamoyl analogue of leucyl-adenylate in the synthetic site and an adduct of amp with 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (an2690) in the editing site
Structure: Aminoacyl-tRNA synthetase. Chain: a. Synonym: leucyl-tRNA synthetase. Engineered: yes
Source: Thermus thermophilus. Organism_taxid: 274. Strain: hb-27. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
1.85Å     R-factor:   0.181     R-free:   0.202
Authors: F.Rock,W.Mao,A.Yaremchuk,M.Tukalo,T.Crepin,H.Zhou,Y.Zhang, V.Hernandez,T.Akama,S.Baker,J.Plattner,L.Shapiro,S.A.Martinis, S.J.Benkovic,S.Cusack,M.R.K.Alley
Key ref:
F.L.Rock et al. (2007). An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science, 316, 1759-1761. PubMed id: 17588934 DOI: 10.1126/science.1142189
Date:
14-May-07     Release date:   03-Jul-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q7SIE4  (Q7SIE4_THETH) -  Leucine--tRNA ligase from Thermus thermophilus
Seq:
Struc: 		 
Seq:
Struc: 		878 a.a.
810 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.6.1.1.4  - leucine--tRNA ligase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: tRNA(Leu) + L-leucine + ATP = L-leucyl-tRNA(Leu) + AMP + diphosphate
tRNA(Leu)
 +
L-leucine
Bound ligand (Het Group name = LEU)
matches with 88.89% similarity 		+ ATP
 =
L-leucyl-tRNA(Leu)
Bound ligand (Het Group name = ANZ)
matches with 69.70% similarity 		+ AMP
 + diphosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1126/science.1142189 Science 316:1759-1761 (2007)
PubMed id: 17588934  
 
 
An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site.
F.L.Rock, W.Mao, A.Yaremchuk, M.Tukalo, T.Crépin, H.Zhou, Y.K.Zhang, V.Hernandez, T.Akama, S.J.Baker, J.J.Plattner, L.Shapiro, S.A.Martinis, S.J.Benkovic, S.Cusack, M.R.Alley.
 
  ABSTRACT  
 
Aminoacyl-transfer RNA (tRNA) synthetases, which catalyze the attachment of the correct amino acid to its corresponding tRNA during translation of the genetic code, are proven antimicrobial drug targets. We show that the broad-spectrum antifungal 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), in development for the treatment of onychomycosis, inhibits yeast cytoplasmic leucyl-tRNA synthetase by formation of a stable tRNA(Leu)-AN2690 adduct in the editing site of the enzyme. Adduct formation is mediated through the boron atom of AN2690 and the 2'- and 3'-oxygen atoms of tRNA's3'-terminal adenosine. The trapping of enzyme-bound tRNA(Leu) in the editing site prevents catalytic turnover, thus inhibiting synthesis of leucyl-tRNA(Leu) and consequentially blocking protein synthesis. This result establishes the editing site as a bona fide target for aminoacyl-tRNA synthetase inhibitors.
 
  Selected figure(s)  
 
Figure 3.
Fig. 3. AN2690 forms an adduct with the terminal adenosine (A76) of tRNA^Leu in the editing active site of LeuRS. (A) Overall structure of the complex of T. thermophilus LeuRS with tRNA^Leu and AN2690, showing the adenosine-AN2690 adduct (ball-and-stick model, ringed in red) in the editing site and leucine (space-filling model) in the synthetic site. The editing domain is cyan; the catalytic domain, yellow; Zn-1 domain, purple; the leucyl-specific insertion domain, black; the anticodon-binding domain, red; the C-terminal domain, gold; zinc atoms, gray spheres; and tRNA, blue tube. (B) Unbiased difference map (1.85 Å resolution) for the AMP-AN2690 adduct in the editing site. (C) Diagram showing water molecules (dark blue spheres) and hydrogen bonds (green dotted lines) between editing site residues of LeuRS and the AMP-AN2690 adduct (orange). Amino acid residues that are mutated in the S. cerevisiae AN2690-resistant mutants are labeled and colored in purple (table S2). The atoms are colored accordingly: boron, mauve; fluorine, green; oxygen, red; nitrogen, light blue; carbon, yellow; and phosphate, purple. (D) Superposition of bound posttransfer editing substrate analog (Nva2AA, brown) (9) and the AMP-AN2690 adduct (orange) obtained after superposing the C positions of the editing domain of each complex. 		Figure 4.
Fig. 4. Boron and the oxaborole ring are required for inhibition of aminoacylation. All reactions were performed in triplicate, and the mean values were used to determine a median inhibitory concentration (IC[50]) with Prism 4 (17).
 
  The above figures are reprinted by permission from the AAAs: Science (2007, 316, 1759-1761) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23263184 H.Zhou, L.Sun, X.L.Yang, and P.Schimmel (2013).
ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase.
  Nature, 494, 121-124.
PDB code: 4hvc
22683997 A.Palencia, T.Crépin, M.T.Vu, T.L.Lincecum, S.A.Martinis, and S.Cusack (2012).
Structural dynamics of the aminoacylation and proofreading functional cycle of bacterial leucyl-tRNA synthetase.
  Nat Struct Mol Biol, 19, 677-684.
PDB codes: 4aq7 4arc 4ari 4as1
20512602 L.Li, L.Yu, and Q.Huang (2011).
Molecular trigger for pre-transfer editing pathway in Valyl-tRNA synthetase: A molecular dynamics simulation study.
  J Mol Model, 17, 555-564.  
20805241 X.Chen, J.J.Ma, M.Tan, P.Yao, Q.H.Hu, G.Eriani, and E.D.Wang (2011).
Modular pathways for editing non-cognate amino acids by human cytoplasmic leucyl-tRNA synthetase.
  Nucleic Acids Res, 39, 235-247.  
21392987 Y.Xia, K.Cao, Y.Zhou, M.R.Alley, F.Rock, M.Mohan, M.Meewan, S.J.Baker, S.Lux, C.Z.Ding, G.Jia, M.Kully, and J.J.Plattner (2011).
Synthesis and SAR of novel benzoxaboroles as a new class of β-lactamase inhibitors.
  Bioorg Med Chem Lett, 21, 2533-2536.  
20546776 A.M.Smith, R.Ammar, C.Nislow, and G.Giaever (2010).
A survey of yeast genomic assays for drug and target discovery.
  Pharmacol Ther, 127, 156-164.  
20660666 B.Nare, S.Wring, C.Bacchi, B.Beaudet, T.Bowling, R.Brun, D.Chen, C.Ding, Y.Freund, E.Gaukel, A.Hussain, K.Jarnagin, M.Jenks, M.Kaiser, L.Mercer, E.Mejia, A.Noe, M.Orr, R.Parham, J.Plattner, R.Randolph, D.Rattendi, C.Rewerts, J.Sligar, N.Yarlett, R.Don, and R.Jacobs (2010).
Discovery of novel orally bioavailable oxaborole 6-carboxamides that demonstrate cure in a murine model of late-stage central nervous system african trypanosomiasis.
  Antimicrob Agents Chemother, 54, 4379-4388.  
21135205 J.M.Becker, S.J.Kauffman, M.Hauser, L.Huang, M.Lin, S.Sillaots, B.Jiang, D.Xu, and T.Roemer (2010).
Pathway analysis of Candida albicans survival and virulence determinants in a murine infection model.
  Proc Natl Acad Sci U S A, 107, 22044-22049.  
20523950 K.Knott, J.Fishovitz, S.B.Thorpe, I.Lee, and W.L.Santos (2010).
N-Terminal peptidic boronic acids selectively inhibit human ClpXP.
  Org Biomol Chem, 8, 3451-3456.  
21058956 M.N.Gwynn, A.Portnoy, S.F.Rittenhouse, and D.J.Payne (2010).
Challenges of antibacterial discovery revisited.
  Ann N Y Acad Sci, 1213, 5.  
19940155 M.Tan, B.Zhu, X.L.Zhou, R.He, X.Chen, G.Eriani, and E.D.Wang (2010).
tRNA-dependent pre-transfer editing by prokaryotic leucyl-tRNA synthetase.
  J Biol Chem, 285, 3235-3244.  
20123733 M.Zhou, X.Dong, N.Shen, C.Zhong, and J.Ding (2010).
Crystal structures of Saccharomyces cerevisiae tryptophanyl-tRNA synthetase: new insights into the mechanism of tryptophan activation and implications for anti-fungal drug design.
  Nucleic Acids Res, 38, 3399-3413.
PDB codes: 3kt0 3kt3 3kt6 3kt8
19941860 S.A.Martinis, and M.T.Boniecki (2010).
The balance between pre- and post-transfer editing in tRNA synthetases.
  FEBS Lett, 584, 455-459.  
20557293 X.L.Zhou, M.Tan, M.Wang, X.Chen, and E.D.Wang (2010).
Post-transfer editing by a eukaryotic leucyl-tRNA synthetase resistant to the broad-spectrum drug AN2690.
  Biochem J, 430, 325-333.  
19796639 A.P.Mascarenhas, and S.A.Martinis (2009).
A glycine hinge for tRNA-dependent translocation of editing substrates to prevent errors by leucyl-tRNA synthetase.
  FEBS Lett, 583, 3443-3447.  
19379069 J.Ling, N.Reynolds, and M.Ibba (2009).
Aminoacyl-tRNA synthesis and translational quality control.
  Annu Rev Microbiol, 63, 61-78.  
19489721 J.W.Kozarich (2009).
The biochemistry of disease: desperately seeking syzygy.
  Annu Rev Biochem, 78, 55-63.  
19188368 K.M.Weimer, B.L.Shane, M.Brunetto, S.Bhattacharyya, and S.Hati (2009).
Evolutionary basis for the coupled-domain motions in Thermus thermophilus leucyl-tRNA synthetase.
  J Biol Chem, 284, 10088-10099.  
19258309 R.A.Hellmann, and S.A.Martinis (2009).
Defects in transient tRNA translocation bypass tRNA synthetase quality control mechanisms.
  J Biol Chem, 284, 11478-11484.  
20042123 T.K.Bhatt, C.Kapil, S.Khan, M.A.Jairajpuri, V.Sharma, D.Santoni, F.Silvestrini, E.Pizzi, and A.Sharma (2009).
A genomic glimpse of aminoacyl-tRNA synthetases in malaria parasite Plasmodium falciparum.
  BMC Genomics, 10, 644.  
19702327 Y.L.Pang, and S.A.Martinis (2009).
A paradigm shift for the amino acid editing mechanism of human cytoplasmic leucyl-tRNA synthetase.
  Biochemistry, 48, 8958-8964.  
19721072 Y.Zeng, H.Roy, P.B.Patil, M.Ibba, and S.Chen (2009).
Characterization of two seryl-tRNA synthetases in albomycin-producing Streptomyces sp. strain ATCC 700974.
  Antimicrob Agents Chemother, 53, 4619-4627.  
18363380 A.P.Mascarenhas, and S.A.Martinis (2008).
Functional segregation of a predicted "hinge" site within the beta-strand linkers of Escherichia coli leucyl-tRNA synthetase.
  Biochemistry, 47, 4808-4816.  
18850722 C.S.Francklyn (2008).
DNA polymerases and aminoacyl-tRNA synthetases: shared mechanisms for ensuring the fidelity of gene expression.
  Biochemistry, 47, 11695-11703.  
18241793 K.E.Splan, K.Musier-Forsyth, M.T.Boniecki, and S.A.Martinis (2008).
In vitro assays for the determination of aminoacyl-tRNA synthetase editing activity.
  Methods, 44, 119-128.  
19020078 M.T.Boniecki, M.T.Vu, A.K.Betha, and S.A.Martinis (2008).
CP1-dependent partitioning of pretransfer and posttransfer editing in leucyl-tRNA synthetase.
  Proc Natl Acad Sci U S A, 105, 19223-19228.  
18682559 S.G.Park, P.Schimmel, and S.Kim (2008).
Aminoacyl tRNA synthetases and their connections to disease.
  Proc Natl Acad Sci U S A, 105, 11043-11049.  
17884461 J.G.Robertson (2007).
Enzymes as a special class of therapeutic target: clinical drugs and modes of action.
  Curr Opin Struct Biol, 17, 674-679.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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