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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); 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. https://doi.org/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. https://doi.org/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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