4EPI

The crystal structure of pesticin-T4 lysozyme hybrid stabilized by engineered disulfide bonds

Summary for 4EPI

• Entry DOI: 10.2210/pdb4epi/pdb
• Related: 4EPA 4EPF 4EXM
• Descriptor: Pesticin, Lysozyme Chimera, SULFATE ION, SODIUM ION, ... (4 entities in total)
• Functional Keywords: bacterial toxin, toxin, hydrolase
• Biological source: Yersinia pestis; More
• Cellular location: Host cytoplasm : P00720
• Total number of polymer chains: 1
• Total formula weight: 37526.43

Authors

Seddiki, N.,Fairman, J.W.,Noinaj, N.,Lukacik, P.,Barnard, T.,Buchanan, S.K. (deposition date: 2012-04-17, release date: 2012-06-20, Last modification date: 2024-10-30)

Primary citation

Lukacik, P.,Barnard, T.J.,Keller, P.W.,Chaturvedi, K.S.,Seddiki, N.,Fairman, J.W.,Noinaj, N.,Kirby, T.L.,Henderson, J.P.,Steven, A.C.,Hinnebusch, B.J.,Buchanan, S.K.
Structural engineering of a phage lysin that targets Gram-negative pathogens.
Proc.Natl.Acad.Sci.USA, 109:9857-9862, 2012

PubMed Abstract: Bacterial pathogens are becoming increasingly resistant to antibiotics. As an alternative therapeutic strategy, phage therapy reagents containing purified viral lysins have been developed against gram-positive organisms but not against gram-negative organisms due to the inability of these types of drugs to cross the bacterial outer membrane. We solved the crystal structures of a Yersinia pestis outer membrane transporter called FyuA and a bacterial toxin called pesticin that targets this transporter. FyuA is a β-barrel membrane protein belonging to the family of TonB dependent transporters, whereas pesticin is a soluble protein with two domains, one that binds to FyuA and another that is structurally similar to phage T4 lysozyme. The structure of pesticin allowed us to design a phage therapy reagent comprised of the FyuA binding domain of pesticin fused to the N-terminus of T4 lysozyme. This hybrid toxin kills specific Yersinia and pathogenic E. coli strains and, importantly, can evade the pesticin immunity protein (Pim) giving it a distinct advantage over pesticin. Furthermore, because FyuA is required for virulence and is more common in pathogenic bacteria, the hybrid toxin also has the advantage of targeting primarily disease-causing bacteria rather than indiscriminately eliminating natural gut flora.

PubMed: 22679291
DOI: 10.1073/pnas.1203472109

Experimental method

X-RAY DIFFRACTION (1.74 Å)