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Crystal Structure of the Bacterial Ribosomal Decoding Site Complexed with a Synthetic Doubly Functionalized Paromomycin Derivative: a New Specific Binding Mode to an A‐Minor Motif Enhances in vitro Antibacterial Activity
Author(s) -
Kondo Jiro,
Pachamuthu Kandasamy,
François Boris,
Szychowski Janek,
Hanessian Stephen,
Westhof Eric
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700113
Subject(s) - ribosome , paromomycin , transfer rna , stereochemistry , binding site , a site , chemistry , biology , rna , biochemistry , aminoglycoside , antibiotics , gene
The crystal structure of the complex between oligonucleotide containing the bacterial ribosomal decoding site (A site) and the synthetic paromomycin analogue 1 , which contains the γ‐amino‐α‐hydroxybutyryl ( L ‐haba) group at position N1 of ring II (2‐DOS ring), and an ether chain with an O ‐phenethylaminoethyl group at position C2′′ of ring III, is reported. Interestingly, next to the paromomycin analogue 1 specifically bound to the A site, a second molecule of 1 with a different conformation is observed at the crystal packing interface which mimics the A‐minor interaction between two bulged‐out adenines from the A site and the codon–anticodon stem of the mRNA–tRNA complex. Improved antibacterial activity supports the conclusion that analogue 1 might affect protein synthesis on the ribosome in two different ways: 1) specific binding to the A site forces maintenance of the “on” state with two bulged out adenines, and 2) a new binding mode of 1 to an A‐minor motif which stabilizes complex formation between the ribosome and the mRNA–tRNA complex regardless of whether the codon–anticodon stem is of the cognate or near‐cognate type.