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

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Vlatko Stojanoski1,2, Banumathi Sankaran3, B V Venkataram Prasad1

  • 1Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.

BMC Biology
|September 23, 2016
PubMed
Abstract

Insights

The MCR-1 enzyme confers resistance to colistin, a last-resort antibiotic. Structural analysis reveals its active site is similar to other phosphoethanolamine transferases, with key residues phosphorylated and zinc ions present.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Microbiology

Background:

  • Colistin is a critical antibiotic for treating multidrug-resistant bacteria due to a lack of novel alternatives.
  • The plasmid-encoded MCR-1 enzyme is the first transferable colistin resistance gene, raising significant public health concerns.
  • MCR-1 is a phosphoethanolamine transferase that modifies lipid A, reducing colistin's effectiveness.

Purpose of the Study:

  • To elucidate the structural basis of colistin resistance conferred by the MCR-1 enzyme.
  • To understand the catalytic mechanism of MCR-1 and its interaction with substrates.

Main Methods:

  • X-ray crystallography was used to determine the structure of the catalytic domain of MCR-1.
  • Structural comparisons were made with related phosphoethanolamine transferases.

Main Results:

  • The high-resolution (1.32 Å) crystal structure of the MCR-1 catalytic domain was determined.
  • The active site of MCR-1 shares similarities with other phosphoethanolamine transferases.
  • Key catalytic residues, including Threonine 285, were found to be phosphorylated, and zinc ions were identified in the active site.

Conclusions:

  • The structure reveals a phosphorylated nucleophile (Threonine 285) and conserved zinc ions within the MCR-1 active site.
  • The absence of apparent binding sites for lipid A and phosphatidylethanolamine in the catalytic domain suggests these interactions occur within the membrane domain.

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