Structure of the catalytic domain of the colistin resistance enzyme MCR-1
Due to the paucity of novel antibiotics, colistin has become a last resort antibiotic for treating multidrug resistant bacteria. Colistin acts by binding the lipid A component of lipopolysaccharides and subsequently disrupting the bacterial membrane. The recently identified plasmid-encoded MCR-1 enzyme is the first transmissible colistin resistance determinant and is a cause for concern for the spread of this resistance trait. MCR-1 is a phosphoethanolamine transferase that catalyzes the addition of phosphoethanolamine to lipid A to decrease colistin affinity. The structure of the catalytic domain of MCR-1 at 1.32 Å reveals the active site is similar to that of related phosphoethanolamine transferases. The putative nucleophile for catalysis, threonine 285, is phosphorylated in cMCR-1 and a zinc is present at a conserved site in addition to three zincs more peripherally located in the active site. As noted for catalytic domains of other phosphoethanolamine transferases, binding sites for the lipid A and phosphatidylethanolamine substrates are not apparent in the cMCR-1 structure, suggesting that they are present in the membrane domain.
- Authors:
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[1]
; [2]
; [3]
; [4]
; [5]
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[1]
- Baylor College of Medicine, Houston, TX (United States). Verna and Marrs McLean Dept. of Biochemistry and Molecular Biology; Baylor College of Medicine, Houston, TX (United States). Dept. of Pharmacology
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Berkeley Center for Structural Biology, Molecular Biophysics and Integrated Bioimaging
- Baylor College of Medicine, Houston, TX (United States). Verna and Marrs McLean Dept. of Biochemistry and Molecular Biology
- Univ. of Fribourg (Switzerland). Lab. of Signal and Image Processing (INSERM), Infection, Antimicrobials, Modelling, Evolution (IAME), Dept. of Medicine, Medical and Molecular Microbiology Emerging Antibiotic Resistance Unit
- Univ. of Fribourg (Switzerland). Lab. of Signal and Image Processing (INSERM), Infection, Antimicrobials, Modelling, Evolution (IAME), Dept. of Medicine, Medical and Molecular Microbiology Emerging Antibiotic Resistance Unit; Univ. of Lausanne (Switzerland). Univ. Hospital Center
- Publication Date:
- Grant/Contract Number:
- AC02-05CH11231; T32 AI55449
- Type:
- Accepted Manuscript
- Journal Name:
- BMC Biology
- Additional Journal Information:
- Journal Volume: 14; Journal Issue: 1; Journal ID: ISSN 1741-7007
- Publisher:
- BioMed Central
- Research Org:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Org:
- USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH); Robert Welch Foundation
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES
- OSTI Identifier:
- 1377497
- Free Publicly Accessible Full Text
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Accepted Manuscript (DOE)
- Publisher's Version of Record
- https://doi.org/10.1186/s12915-016-0303-0