Structural basis for the methylation of G1405 in 16S rRNA by aminoglycoside resistance methyltransferase Sgm from an antibiotic producer: a diversity of active sites in m 7 G methyltransferases
| Autor: | Nilofer Husain, Gordana Maravić-Vlahoviček, Karolina L. Tkaczuk, J. Sivaraman, Katarzyna H. Kaminska, Sonja Čubrilo, Shenoy Rajesh Tulsidas, Janusz M. Bujnicki |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular S-Adenosylmethionine Methyltransferase Molecular Sequence Data Ribosome Subunits Small Bacterial Calorimetry Biology Methylation Micromonospora 03 medical and health sciences Bacterial Proteins Structural Biology Catalytic Domain RNA Ribosomal 16S Drug Resistance Bacterial Genetics medicine Amino Acid Sequence Conserved Sequence 030304 developmental biology 2. Zero hunger 0303 health sciences Base Sequence Sequence Homology Amino Acid 030306 microbiology Aminoglycoside Methyltransferases antibiotic resistance methyltransferase Sgm aminoglycosides gentamicin sisomicin Ribosomal RNA biology.organism_classification S-Adenosylhomocysteine Footprinting Anti-Bacterial Agents 3. Good health Aminoglycosides Biochemistry Sisomicin Horizontal gene transfer medicine.drug |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | Sgm (Sisomicin-gentamicin methyltransferase) from antibiotic-producing bacterium Micromonospora zionensis is an enzyme that confers resistance to aminoglycosides like gentamicin and sisomicin by specifically methylating G1405 in bacterial 16S rRNA. Sgm belongs to the aminoglycoside resistance methyltransferase (Arm) family of enzymes that have been recently found to spread by horizontal gene transfer among disease-causing bacteria. Structural characterization of Arm enzymes is the key to understand their mechanism of action and to develop inhibitors that would block their activity. Here we report the structure of Sgm in complex with cofactors S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy) at 2.0 and 2.1 Å resolution, respectively, and results of mutagenesis and rRNA footprinting, and protein-substrate docking. We propose the mechanism of methylation of G1405 by Sgm and compare it with other m 7 G methyltransferases, revealing a surprising diversity of active sites and binding modes for the same basic reaction of RNA modification. This analysis can serve as a stepping stone towards developing drugs that would specifically block the activity of Arm methyltransferases and thereby re-sensitize pathogenic bacteria to aminoglycoside antibiotics. |
| Databáze: | OpenAIRE |
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