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Structures of aminoarabinose transferase ArnT suggest a molecular basis for lipid A glycosylation. Science 2016 Feb 05;351(6273):608-12

Date

02/26/2016

Pubmed ID

26912703

Pubmed Central ID

PMC4963604

DOI

10.1126/science.aad1172

Scopus ID

2-s2.0-84957545547 (requires institutional sign-in at Scopus site)   90 Citations

Abstract

Polymyxins are antibiotics used in the last line of defense to combat multidrug-resistant infections by Gram-negative bacteria. Polymyxin resistance arises through charge modification of the bacterial outer membrane with the attachment of the cationic sugar 4-amino-4-deoxy-l-arabinose to lipid A, a reaction catalyzed by the integral membrane lipid-to-lipid glycosyltransferase 4-amino-4-deoxy-L-arabinose transferase (ArnT). Here, we report crystal structures of ArnT from Cupriavidus metallidurans, alone and in complex with the lipid carrier undecaprenyl phosphate, at 2.8 and 3.2 angstrom resolution, respectively. The structures show cavities for both lipidic substrates, which converge at the active site. A structural rearrangement occurs on undecaprenyl phosphate binding, which stabilizes the active site and likely allows lipid A binding. Functional mutagenesis experiments based on these structures suggest a mechanistic model for ArnT family enzymes.

Author List

Petrou VI, Herrera CM, Schultz KM, Clarke OB, Vendome J, Tomasek D, Banerjee S, Rajashankar KR, Belcher Dufrisne M, Kloss B, Kloppmann E, Rost B, Klug CS, Trent MS, Shapiro L, Mancia F

Authors

Candice S. Klug PhD Professor in the Biophysics department at Medical College of Wisconsin
Kathryn M. Schultz Research Scientist I in the Biophysics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Amino Sugars
Arabinose
Bacterial Proteins
Catalysis
Catalytic Domain
Crystallography, X-Ray
Cupriavidus
Glycosylation
Lipid A
Mutagenesis
Mutation
Pentosyltransferases
Polyisoprenyl Phosphates
Polymyxins
Protein Binding
Protein Structure, Secondary
Protein Structure, Tertiary
Substrate Specificity