2V0C

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

Summary for 2V0C

• Entry DOI: 10.2210/pdb2v0c/pdb
• Related: 1H3N 1OBC 1OBH 2BTE 2BYT
• Descriptor: AMINOACYL-TRNA SYNTHETASE, LEUCINE, [(2R,3S,4R,5R)-5-(6-AMINO-9H-PURIN-9-YL)-3,4-DIHYDROXYTETRAHYDRO-2-FURANYL]METHYL SULFAMATE, ... (7 entities in total)
• Functional Keywords: ligase, nucleotide-binding, protein biosynthesis, clss i aminoacyl- trna synthetase, atp + l-leucine + trna (leu) gives amp + ppi + l-leucyl-trna(leu), aminoacyl-trna synthetase, zinc, atp-binding, metal-binding
• Biological source: THERMUS THERMOPHILUS
• Total number of polymer chains: 1
• Total formula weight: 102566.67

Authors

Rock, F.,Mao, W.,Yaremchuk, A.,Tukalo, M.,Crepin, T.,Zhou, H.,Zhang, Y.,Hernandez, V.,Akama, T.,Baker, S.,Plattner, J.,Shapiro, L.,Martinis, S.A.,Benkovic, S.J.,Cusack, S.,Alley, M.R.K. (deposition date: 2007-05-14, release date: 2007-07-03, Last modification date: 2023-12-13)

Primary citation

Rock, F.,Mao, W.,Yaremchuk, A.,Tukalo, M.,Crepin, T.,Zhou, H.,Zhang, Y.,Hernandez, V.,Akama, T.,Baker, S.,Plattner, J.,Shapiro, L.,Martinis, S.A.,Benkovic, S.J.,Cusack, S.,Alley, M.R.K.
An Antifungal Agent Inhibits an Aminoacyl-tRNA Synthetase by Trapping tRNA in the Editing Site.
Science, 316:1759-, 2007

PubMed 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.

PubMed: 17588934
DOI: 10.1126/SCIENCE.1142189

Experimental method

X-RAY DIFFRACTION (1.85 Å)