Structural insights into the function of aminoglycoside-resistance A1408 16S rRNA methyltransferases from antibiotic-producing and human pathogenic bacteria.

Nucleic Acids Research
Rachel MacmasterGraeme L Conn

Abstract

X-ray crystal structures were determined of the broad-spectrum aminoglycoside-resistance A1408 16S rRNA methyltransferases KamB and NpmA, from the aminoglycoside-producer Streptoalloteichus tenebrarius and human pathogenic Escherichia coli, respectively. Consistent with their common function, both are Class I methyltransferases with additional highly conserved structural motifs that embellish the core SAM-binding fold. In overall structure, the A1408 rRNA methyltransferase were found to be most similar to a second family of Class I methyltransferases of distinct substrate specificity (m(7)G46 tRNA). Critical residues for A1408 rRNA methyltransferase activity were experimentally defined using protein mutagenesis and bacterial growth assays with kanamycin. Essential residues for SAM coenzyme binding and an extended protein surface that likely interacts with the 30S ribosomal subunit were thus revealed. The structures also suggest potential mechanisms of A1408 target nucleotide selection and positioning. We propose that a dynamic extended loop structure that is positioned adjacent to both the bound SAM and a functionally critical structural motif may mediate concerted conformational changes in rRNA and protein that underpin the sp...Continue Reading

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Citations

Apr 11, 2014·Proceedings of the National Academy of Sciences of the United States of America·Jack A DunkleChristine M Dunham
Feb 16, 2016·MedChemComm·Sylvie Garneau-Tsodikova, Kristin J Labby
Jun 8, 2012·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Jun-ichi Wachino, Yoshichika Arakawa
Apr 16, 2013·Plasmid·Sonja ObranićGordana Maravić-Vlahoviček
Mar 16, 2017·Antimicrobial Agents and Chemotherapy·Kellie Vinal, Graeme L Conn
Sep 30, 2015·Antimicrobial Agents and Chemotherapy·Natalia ZelinskayaGraeme L Conn
Jan 29, 2019·The Journal of Antimicrobial Chemotherapy·Stefan RiedelJames E Kirby
Feb 23, 2020·Nucleic Acids Research·Felix HagelskampStefanie Kellner
Dec 8, 2020·Biochemistry. Biokhimii︠a︡·I A OstermanP V Sergiev

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Methods Mentioned

BETA
chemical modification
gel filtration
X-ray

Software Mentioned

HKL2000
FlowerPower
BLAST
Dali
Phenix
Coot
Phaser
HADDOCK
wARP
ARP

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