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

Abstract

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:
 [1];  [2];  [3];  [4];  [5]; ORCiD logo [1]
  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
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Berkeley Center for Structural Biology, Molecular Biophysics and Integrated Bioimaging
  3. Baylor College of Medicine, Houston, TX (United States). Verna and Marrs McLean Dept. of Biochemistry and Molecular Biology
  4. 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
  5. 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:
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
OSTI Identifier:
1377497
Grant/Contract Number:  
AC02-05CH11231; T32 AI55449
Resource Type:
Accepted Manuscript
Journal Name:
BMC Biology
Additional Journal Information:
Journal Volume: 14; Journal Issue: 1; Journal ID: ISSN 1741-7007
Publisher:
BioMed Central
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

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., 2016. Web. doi:10.1186/s12915-016-0303-0.
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.
Stojanoski, Vlatko, Sankaran, Banumathi, Prasad, B. V. Venkataram, Poirel, Laurent, Nordmann, Patrice, and Palzkill, Timothy. Wed . "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.
@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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    Works referencing / citing this record:

    Automatic protein structure solution from weak X-ray data
    journal, November 2013

    • Skubák, Pavol; Pannu, Navraj S.
    • Nature Communications, Vol. 4, Issue 1
    • DOI: 10.1038/ncomms3777

    Colistin: The Revival of Polymyxins for the Management of Multidrug-Resistant Gram-Negative Bacterial Infections
    journal, May 2005

    • Falagas, M. E.; Kasiakou, S. K.; Saravolatz, L. D.
    • Clinical Infectious Diseases, Vol. 40, Issue 9
    • DOI: 10.1086/429323

    Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria
    journal, November 2014


    Plasmid-mediated colistin resistance: an additional antibiotic resistance menace
    journal, May 2016


    ThreaDom: extracting protein domain boundary information from multiple threading alignments
    journal, June 2013


    Structures of aminoarabinose transferase ArnT suggest a molecular basis for lipid A glycosylation
    journal, February 2016


    The Structure of the Neisserial Lipooligosaccharide Phosphoethanolamine Transferase A (LptA) Required for Resistance to Polymyxin
    journal, September 2013

    • Wanty, Christopher; Anandan, Anandhi; Piek, Susannah
    • Journal of Molecular Biology, Vol. 425, Issue 18
    • DOI: 10.1016/j.jmb.2013.06.029

    I-TASSER: a unified platform for automated protein structure and function prediction
    journal, March 2010

    • Roy, Ambrish; Kucukural, Alper; Zhang, Yang
    • Nature Protocols, Vol. 5, Issue 4
    • DOI: 10.1038/nprot.2010.5

    Plasmid-Mediated Colistin-Resistant Escherichia coli in Bacteremia in Switzerland
    journal, March 2016

    • Nordmann, Patrice; Lienhard, Reto; Kieffer, Nicolas
    • Clinical Infectious Diseases, Vol. 62, Issue 10
    • DOI: 10.1093/cid/ciw124

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    • Falagas, Matthew E.; Rafailidis, Petros I.; Matthaiou, Dimitrios K.
    • Drug Resistance Updates, Vol. 13, Issue 4-5
    • DOI: 10.1016/j.drup.2010.05.002

    Use of bacteriophage T7 RNA polymerase to direct selective high-level expression of cloned genes
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    • Needham, Brittany D.; Trent, M. Stephen
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    • DOI: 10.1038/nrmicro3047

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