4.8 Article

Reprogramming Human Siderocalin To Neutralize Petrobactin, the Essential Iron Scavenger of Anthrax Bacillus

期刊

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 57, 期 44, 页码 14619-14623

出版社

WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201807442

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anticalin; iron chelator; lipocalin; protein engineering; siderophore

资金

  1. Helmholtz-Zentrum Berlin

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Bacillus anthracis owes its pronounced virulence-apart from specific toxins-to a twofold import mechanism for Fe-III 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 center dot Fe-III instead of BB center dot Fe-III, and with even higher affinity (K-D approximate to 20 pM). X-ray crystallographic analysis of the resulting petrocalin in complex with PB center dot Ga-III 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.

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