Substrate Recognition by a Colistin Resistance Enzyme from Moraxella catarrhalis
| Autor: | Georgina Cox, Elena Evdokimova, Peter J. Stogios, Zdzislaw Wawrzak, Gerard D. Wright, Haley L. Zubyk, Alexei Savchenko |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Protein Conformation 030106 microbiology Transferases (Other Substituted Phosphate Groups) Crystallography X-Ray medicine.disease_cause Biochemistry Article Substrate Specificity Lipid A Moraxella catarrhalis 03 medical and health sciences medicine Transferase Polymyxins Gene biology Colistin Chemistry Pathogenic bacteria General Medicine biology.organism_classification Enterobacteriaceae Anti-Bacterial Agents 030104 developmental biology Drug Resistance Neoplasm Molecular Medicine Dimerization Bacteria medicine.drug |
| Zdroj: | ACS Chemical Biology. 13:1322-1332 |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/acschembio.8b00116 |
| Popis: | Lipid A phosphoethanolamine (PEtN) transferases render bacteria resistant to the last resort antibiotic colistin. The recent discoveries of pathogenic bacteria harboring plasmid-borne PEtN transferase (mcr) genes have illustrated the serious potential for wide dissemination of these resistance elements. The origin of mcr-1 is traced to Moraxella species co-occupying environmental niches with Enterobacteriaceae. Here, we describe the crystal structure of the catalytic domain of the chromosomally encoded colistin resistance PEtN transferase, ICRMc (for intrinsic colistin resistance) of Moraxella catarrhalis. The ICRMc structure in complex with PEtN reveals key molecular details including specific residues involved in catalysis and PEtN binding. It also demonstrates that ICRMc catalytic domain dimerization is required for substrate binding. Our structure-guided phylogenetic analysis provides sequence signatures defining potentially colistin-active representatives in this enzyme family. Combined, these results advance the molecular and mechanistic understanding of PEtN transferases and illuminate their origins. |
| Databáze: | OpenAIRE |
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