Reprogramming Human Siderocalin To Neutralize Petrobactin, the Essential Iron Scavenger of Anthrax Bacillus
| Autor: | Arne Skerra, Martin Dauner, Genia Lücking, Andreas Eichinger, Siegfried Scherer |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Siderophore Iron Protein design Bacillus cereus Bacillibactin Siderocalin 010402 general chemistry Ligands 01 natural sciences Catalysis Microbiology 03 medical and health sciences chemistry.chemical_compound Bacterial Proteins Lipocalin-2 Humans biology Chemistry General Chemistry Protein engineering biology.organism_classification Ligand (biochemistry) 0104 chemical sciences Bacillus anthracis 030104 developmental biology Benzamides Carrier Proteins |
| Zdroj: | Angewandte Chemie (International ed. in English). 57(44) |
| ISSN: | 1521-3773 |
| Popis: | Bacillus anthracis owes its pronounced virulence-apart from specific toxins-to a twofold import mechanism for FeIII ions. This pathogenic bacterium secretes the siderophores bacillibactin (BB) and petrobactin (PB), of which only BB is neutralized by human siderocalin, an abundant lipocalin in plasma. We describe its reshaping via combinatorial protein design to bind PB⋅FeIII instead of BB⋅FeIII , and with even higher affinity (KD ≈20 pm). X-ray crystallographic analysis of the resulting "petrocalin" in complex with PB⋅GaIII reveals a positively charged ligand pocket while the extended butterfly-like conformation of the bound PB provides a rationale for the missing recognition by the natural siderocalin. In microbiological studies, a combination of petrocalin and siderocalin effectively suppressed the growth of a BB+ /PB+ strain of Bacillus cereus under iron-limiting culture conditions. Thus, our reprogrammed lipocalin may offer novel treatment options for devastating infections caused by B. anthracis. |
| Databáze: | OpenAIRE |
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