Abstract
With bacterial resistance becoming a serious threat to global public health, antimicrobial peptides (AMPs) have become a promising area of focus in antibiotic research. AMPs are derived from a diverse range of species, from prokaryotes to humans, with a mechanism of action that often involves disruption of the bacterial cell membrane. Proline-rich antimicrobial peptides (PrAMPs) are instead actively transported inside the bacterial cell where they bind and inactivate specific targets. Recently, it was reported that some PrAMPs, such as Bac71-35, oncocins and apidaecins, bind and inactivate the bacterial ribosome. Here we report the crystal structures of Bac71-35, Pyrrhocoricin, Metalnikowin and two oncocin derivatives, bound to the Thermus thermophilus 70S ribosome. Each of the PrAMPs blocks the peptide exit tunnel of the ribosome by simultaneously occupying three well characterized antibiotic-binding sites and interferes with the initiation step of translation, thereby revealing a common mechanism of action used by these PrAMPs to inactivate protein synthesis. Our study expands the repertoire of PrAMPs and provides a framework for designing new-generation therapeutics.
| Original language | English (US) |
|---|---|
| Article number | 18 |
| Pages (from-to) | 2439-2450 |
| Number of pages | 12 |
| Journal | Nucleic Acids Research |
| Volume | 44 |
| Issue number | 5 |
| DOIs | |
| State | Published - Jan 24 2016 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Genetics
Cite this
Structures of proline-rich peptides bound to the ribosome reveal a common mechanism of protein synthesis inhibition. / Gagnon, Matthieu; Roy, Raktim N.; Lomakin, Ivan B.; Florin, Tanja; Mankin, Alexander S.; Steitz, Thomas A.
In: Nucleic Acids Research, Vol. 44, No. 5, 18, 24.01.2016, p. 2439-2450.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Structures of proline-rich peptides bound to the ribosome reveal a common mechanism of protein synthesis inhibition
AU - Gagnon, Matthieu
AU - Roy, Raktim N.
AU - Lomakin, Ivan B.
AU - Florin, Tanja
AU - Mankin, Alexander S.
AU - Steitz, Thomas A.
PY - 2016/1/24
Y1 - 2016/1/24
N2 - With bacterial resistance becoming a serious threat to global public health, antimicrobial peptides (AMPs) have become a promising area of focus in antibiotic research. AMPs are derived from a diverse range of species, from prokaryotes to humans, with a mechanism of action that often involves disruption of the bacterial cell membrane. Proline-rich antimicrobial peptides (PrAMPs) are instead actively transported inside the bacterial cell where they bind and inactivate specific targets. Recently, it was reported that some PrAMPs, such as Bac71-35, oncocins and apidaecins, bind and inactivate the bacterial ribosome. Here we report the crystal structures of Bac71-35, Pyrrhocoricin, Metalnikowin and two oncocin derivatives, bound to the Thermus thermophilus 70S ribosome. Each of the PrAMPs blocks the peptide exit tunnel of the ribosome by simultaneously occupying three well characterized antibiotic-binding sites and interferes with the initiation step of translation, thereby revealing a common mechanism of action used by these PrAMPs to inactivate protein synthesis. Our study expands the repertoire of PrAMPs and provides a framework for designing new-generation therapeutics.
AB - With bacterial resistance becoming a serious threat to global public health, antimicrobial peptides (AMPs) have become a promising area of focus in antibiotic research. AMPs are derived from a diverse range of species, from prokaryotes to humans, with a mechanism of action that often involves disruption of the bacterial cell membrane. Proline-rich antimicrobial peptides (PrAMPs) are instead actively transported inside the bacterial cell where they bind and inactivate specific targets. Recently, it was reported that some PrAMPs, such as Bac71-35, oncocins and apidaecins, bind and inactivate the bacterial ribosome. Here we report the crystal structures of Bac71-35, Pyrrhocoricin, Metalnikowin and two oncocin derivatives, bound to the Thermus thermophilus 70S ribosome. Each of the PrAMPs blocks the peptide exit tunnel of the ribosome by simultaneously occupying three well characterized antibiotic-binding sites and interferes with the initiation step of translation, thereby revealing a common mechanism of action used by these PrAMPs to inactivate protein synthesis. Our study expands the repertoire of PrAMPs and provides a framework for designing new-generation therapeutics.
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U2 - 10.1093/nar/gkw018
DO - 10.1093/nar/gkw018
M3 - Article
VL - 44
SP - 2439
EP - 2450
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 5
M1 - 18
ER -