Structure of the catalytic domain of the colistin resistance enzyme MCR-1

doi:10.1186/s12915-016-0303-0

Title: 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:

Stojanoski, Vlatko ^[1] ; Sankaran, Banumathi ^[2] ; Prasad, B. V. Venkataram ^[3] ; Poirel, Laurent ^[4] ; Nordmann, Patrice ^[5] ;

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:: 2016-09-21

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


                    Stojanoski, Vlatko, Sankaran, Banumathi, Prasad, B. V.  Venkataram, Poirel, Laurent, Nordmann, Patrice, and Palzkill, Timothy. Structure of the catalytic domain of the colistin resistance enzyme MCR-1.  United States: N. p.,  
        Web.  doi:10.1186/s12915-016-0303-0.

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                    Stojanoski, Vlatko, Sankaran, Banumathi, Prasad, B. V.  Venkataram, Poirel, Laurent, Nordmann, Patrice, & Palzkill, Timothy. Structure of the catalytic domain of the colistin resistance enzyme MCR-1.  United States.  doi:10.1186/s12915-016-0303-0.

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                    Stojanoski, Vlatko, Sankaran, Banumathi, Prasad, B. V.  Venkataram, Poirel, Laurent, Nordmann, Patrice, and Palzkill, Timothy. 2016.  
        "Structure of the catalytic domain of the colistin resistance enzyme MCR-1".  United States.  
        doi:10.1186/s12915-016-0303-0.  https://www.osti.gov/servlets/purl/1377497.

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@article{osti_1377497,

  title        = {Structure of the catalytic domain of the colistin resistance enzyme MCR-1},

  author       = {Stojanoski, Vlatko and Sankaran, Banumathi and Prasad, B. V.  Venkataram and Poirel, Laurent and Nordmann, Patrice and Palzkill, Timothy},

  abstractNote = {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.},

  doi          = {10.1186/s12915-016-0303-0},

  journal      = {BMC Biology},

  number       = 1,

  volume       = 14,

  place        = {United States},

  year         = {2016},

  month        = {9}

}

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10.1186/s12915-016-0303-0
https://doi.org/10.1186/s12915-016-0303-0

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