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BMC Biol. 2016 Sep 21;14(1):81.

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

Author information

1
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
2
Department of Pharmacology, Baylor College of Medicine, Houston, TX, 77030, USA.
3
Berkeley Center for Structural Biology, Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley Laboratory, 1 Cyclotron Road, Berkeley, CA, 94720, USA.
4
Department of Medicine, Medical and Molecular Microbiology "Emerging Antibiotic Resistance" Unit and European INSERM Laboratory, IAME, University of Fribourg, Fribourg, Switzerland.
5
University of Lausanne, University Hospital Center, Lausanne, Switzerland.
6
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. timothyp@bcm.edu.
7
Department of Pharmacology, Baylor College of Medicine, Houston, TX, 77030, USA. timothyp@bcm.edu.

Abstract

BACKGROUND:

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.

RESULTS:

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.

CONCLUSIONS:

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.

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