5FDU

Crystal structure of the Metalnikowin I antimicrobial peptide bound to the Thermus thermophilus 70S ribosome

This is a non-PDB format compatible entry.

Summary for 5FDU

• Entry DOI: 10.2210/pdb5fdu/pdb
• Descriptor: 23S ribosomal RNA, 50S ribosomal protein L14, 50S ribosomal protein L15, ... (59 entities in total)
• Functional Keywords: bacterial ribosome, proline-rich antimicrobial peptide, antibiotics, protein biosynthesis, ribosome
• Biological source: Escherichia coli (strain K12); More
• Total number of polymer chains: 108
• Total formula weight: 4368310.47

Authors

Seefeldt, A.C.,Graf, M.,Perebaskine, N.,Nguyen, F.,Arenz, S.,Mardirossian, M.,Scocchi, M.,Wilson, D.N.,Innis, C.A. (deposition date: 2015-12-16, release date: 2016-01-27, Last modification date: 2024-04-24)

Primary citation

Seefeldt, A.C.,Graf, M.,Perebaskine, N.,Nguyen, F.,Arenz, S.,Mardirossian, M.,Scocchi, M.,Wilson, D.N.,Innis, C.A.
Structure of the mammalian antimicrobial peptide Bac7(1-16) bound within the exit tunnel of a bacterial ribosome.
Nucleic Acids Res., 44:2429-2438, 2016

PubMed Abstract: Proline-rich antimicrobial peptides (PrAMPs) produced as part of the innate immune response of animals, insects and plants represent a vast, untapped resource for the treatment of multidrug-resistant bacterial infections. PrAMPs such as oncocin or bactenecin-7 (Bac7) interact with the bacterial ribosome to inhibit translation, but their supposed specificity as inhibitors of bacterial rather than mammalian protein synthesis remains unclear, despite being key to developing drugs with low toxicity. Here, we present crystal structures of the Thermus thermophilus 70S ribosome in complex with the first 16 residues of mammalian Bac7, as well as the insect-derived PrAMPs metalnikowin I and pyrrhocoricin. The structures reveal that the mammalian Bac7 interacts with a similar region of the ribosome as insect-derived PrAMPs. Consistently, Bac7 and the oncocin derivative Onc112 compete effectively with antibiotics, such as erythromycin, which target the ribosomal exit tunnel. Moreover, we demonstrate that Bac7 allows initiation complex formation but prevents entry into the elongation phase of translation, and show that it inhibits translation on both mammalian and bacterial ribosomes, explaining why this peptide needs to be stored as an inactive pro-peptide. These findings highlight the need to consider the specificity of PrAMP derivatives for the bacterial ribosome in future drug development efforts.

PubMed: 26792896
DOI: 10.1093/nar/gkv1545

Experimental method

X-RAY DIFFRACTION (2.9 Å)