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| Title | Structural basis of undecaprenyl phosphate glycosylation leading to polymyxin resistance in Gram-negative bacteria. |
|---|---|
| Journal, issue, pages | bioRxiv, Year 2025 |
| Publish date | Jan 30, 2025 |
Authors | Khuram U Ashraf / Mariana Bunoro-Batista / T Bertie Ansell / Ankita Punetha / Stephannie Rosario-Garrido / Emre Firlar / Jason T Kaelber / Phillip J Stansfeld / Vasileios I Petrou / ![]() |
| PubMed Abstract | In Gram-negative bacteria, the enzymatic modification of Lipid A with aminoarabinose (L-Ara4N) leads to resistance against polymyxin antibiotics and cationic antimicrobial peptides. ArnC, an integral ...In Gram-negative bacteria, the enzymatic modification of Lipid A with aminoarabinose (L-Ara4N) leads to resistance against polymyxin antibiotics and cationic antimicrobial peptides. ArnC, an integral membrane glycosyltransferase, attaches a formylated form of aminoarabinose to the lipid undecaprenyl phosphate, enabling its association with the bacterial inner membrane. Here, we present cryo-electron microscopy structures of ArnC from in and nucleotide-bound conformations. These structures reveal a conformational transition that takes place upon binding of the partial donor substrate. Using coarse-grained and atomistic simulations, we provide insights into substrate coordination before and during catalysis, and we propose a catalytic mechanism that may operate on all similar metal-dependent polyprenyl phosphate glycosyltransferases. The reported structures provide a new target for drug design aiming to combat polymyxin resistance. |
External links | bioRxiv / PubMed:39974898 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.74 - 2.96 Å |
| Structure data | EMDB-43617, PDB-8vxh: EMDB-43812, PDB-9asc: EMDB-44302, PDB-9b77: |
| Chemicals | ![]() ChemComp-UDP: ![]() ChemComp-MN: ![]() ChemComp-HOH: |
| Source |
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Keywords | TRANSFERASE / Glycosyltransferase / undecaprenyl phosphate / aminoarabinose / polymyxin resistance / GT-A |
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salmonella enterica subsp. enterica serovar typhimurium str. lt2 (bacteria)
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