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Science. 2016 Feb 5;351(6273):608-12. doi: 10.1126/science.aad1172.

Structures of aminoarabinose transferase ArnT suggest a molecular basis for lipid A glycosylation.

Author information

1
Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA.
2
Department of Infectious Diseases, University of Georgia, College of Veterinary Medicine, Athens, GA 30602, USA.
3
Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
4
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
5
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. Department of Systems Biology, Columbia University, New York, NY 10032, USA.
6
Department of Chemistry and Chemical Biology, Cornell University, Northeastern Collaborative Access Team, Advanced Photon Source, Argonne, IL 60439, USA.
7
New York Consortium on Membrane Protein Structure, New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA.
8
Department of Informatics, Bioinformatics and Computational Biology, Technische Universität München, Boltzmannstrasse 3, 85748 Garching, Germany.
9
Department of Informatics, Bioinformatics and Computational Biology, Technische Universität München, Boltzmannstrasse 3, 85748 Garching, Germany. Institute for Advanced Study (TUM-IAS), Technische Universität München, Boltzmannstrasse 3, 85748 Garching, Germany.
10
Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA. fm123@cumc.columbia.edu.

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.

PMID:
26912703
PMCID:
PMC4963604
DOI:
10.1126/science.aad1172
[Indexed for MEDLINE]
Free PMC Article

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