Publication Date:
2016-02-26
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Petrou, Vasileios I -- Herrera, Carmen M -- Schultz, Kathryn M -- Clarke, Oliver B -- Vendome, Jeremie -- Tomasek, David -- Banerjee, Surajit -- Rajashankar, Kanagalaghatta R -- Belcher Dufrisne, Meagan -- Kloss, Brian -- Kloppmann, Edda -- Rost, Burkhard -- Klug, Candice S -- Trent, M Stephen -- Shapiro, Lawrence -- Mancia, Filippo -- AI064184/AI/NIAID NIH HHS/ -- AI076322/AI/NIAID NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- R01 GM111980/GM/NIGMS NIH HHS/ -- S10 RR029205/RR/NCRR NIH HHS/ -- U54 GM095315/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2016 Feb 5;351(6273):608-12. doi: 10.1126/science.aad1172.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA. ; Department of Infectious Diseases, University of Georgia, College of Veterinary Medicine, Athens, GA 30602, USA. ; Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI 53226, USA. ; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. ; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. Department of Systems Biology, Columbia University, New York, NY 10032, USA. ; Department of Chemistry and Chemical Biology, Cornell University, Northeastern Collaborative Access Team, Advanced Photon Source, Argonne, IL 60439, USA. ; New York Consortium on Membrane Protein Structure, New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA. ; Department of Informatics, Bioinformatics and Computational Biology, Technische Universitat Munchen, Boltzmannstrasse 3, 85748 Garching, Germany. ; Department of Informatics, Bioinformatics and Computational Biology, Technische Universitat Munchen, Boltzmannstrasse 3, 85748 Garching, Germany. Institute for Advanced Study (TUM-IAS), Technische Universitat Munchen, Boltzmannstrasse 3, 85748 Garching, Germany. ; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA. fm123@cumc.columbia.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912703" target="_blank"〉PubMed〈/a〉
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
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Chemistry and Pharmacology
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Computer Science
,
Medicine
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Natural Sciences in General
,
Physics
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