Structures of aminoarabinose transferase ArnT suggest a molecular basis for lipid A glycosylation
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...
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Published in | Science (American Association for the Advancement of Science) Vol. 351; no. 6273; pp. 608 - 612 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Association for the Advancement of Science
05.02.2016
The American Association for the Advancement of Science AAAS |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Office of Research Infrastructure Programs (ORIP) P41 GM103403; S10 RR029205; R01 GM111980; AI064184; AI076322; W911NF-12-1-0390 National Institutes of Health (NIH) US Army Research Office (ARO) National Institute of General Medical Sciences (NIGMS) These authors contributed equally to this work. |
ISSN: | 0036-8075 1095-9203 |
DOI: | 10.1126/science.aad1172 |