3WRU

Crystal structure of the bacterial ribosomal decoding site in complex with synthetic aminoglycoside with F-HABA group

Summary for 3WRU

• Entry DOI: 10.2210/pdb3wru/pdb
• Descriptor: RNA (5'-R(*UP*UP*GP*CP*GP*UP*CP*AP*CP*GP*CP*CP*GP*GP*CP*GP*AP*AP*GP*UP*CP*GP*C)-3'), (2R,3R)-4-amino-N-[(1R,2S,3R,4R,5S)-5-amino-4-[(2,6-diamino-2,3,4,6-tetradeoxy-alpha-D-erythro-hexopyranosyl)oxy]-3-{[3-O-(2,6-diamino-2,3,4,6-tetradeoxy-beta-L-threo-hexopyranosyl)-beta-D-ribofuranosyl]oxy}-2-hydroxycyclohexyl]-3-fluoro-2-hydroxybutanamide, POTASSIUM ION, ... (4 entities in total)
• Functional Keywords: ribosomal rna, aminoglycoside, rna-antibiotic complex, rna/antibiotic
• Total number of polymer chains: 2
• Total formula weight: 16119.43

Authors

Maianti, J.P.,Kanazawa, H.,Dozzo, P.,Feeney, L.A.,Armstrong, E.S.,Kondo, J.,Hanessian, S. (deposition date: 2014-02-27, release date: 2014-11-05, Last modification date: 2024-03-20)

Primary citation

Maianti, J.P.,Kanazawa, H.,Dozzo, P.,Matias, R.D.,Feeney, L.A.,Armstrong, E.S.,Hildebrandt, D.J.,Kane, T.R.,Gliedt, M.J.,Goldblum, A.A.,Linsell, M.S.,Aggen, J.B.,Kondo, J.,Hanessian, S.
Toxicity Modulation, Resistance Enzyme Evasion, and A-Site X-ray Structure of Broad-Spectrum Antibacterial Neomycin Analogs
Acs Chem.Biol., 9:2067-2073, 2014

PubMed Abstract: Aminoglycoside antibiotics are pseudosaccharides decorated with ammonium groups that are critical for their potent broad-spectrum antibacterial activity. Despite over three decades of speculation whether or not modulation of pKa is a viable strategy to curtail aminoglycoside kidney toxicity, there is a lack of methods to systematically probe amine-RNA interactions and resultant cytotoxicity trends. This study reports the first series of potent aminoglycoside antibiotics harboring fluorinated N1-hydroxyaminobutyryl acyl (HABA) appendages for which fluorine-RNA contacts are revealed through an X-ray cocrystal structure within the RNA A-site. Cytotoxicity in kidney-derived cells was significantly reduced for the derivative featuring our novel β,β-difluoro-HABA group, which masks one net charge by lowering the pKa without compromising antibacterial potency. This novel side-chain assists in evasion of aminoglycoside-modifying enzymes, and it can be easily transferred to impart these properties onto any number of novel analogs.

PubMed: 25019242
DOI: 10.1021/cb5003416

Experimental method

X-RAY DIFFRACTION (2.3 Å)