TY - JOUR
T1 - Structures of proline-rich peptides bound to the ribosome reveal a common mechanism of protein synthesis inhibition
AU - Gagnon, Matthieu G.
AU - Roy, Raktim N.
AU - Lomakin, Ivan B.
AU - Florin, Tanja
AU - Mankin, Alexander S.
AU - Steitz, Thomas A.
N1 - Funding Information:
Howard Hughes Medical Institute and National Institutes of Health [GM022778 to T.A.S.]; National Institutes of Health [GM106386 to A.S.M.]; National Institute of General Medical Sciences [P41GM103403 to the North East Collaborative Access Teams (NE-CAT) at the Advanced Photon Source (beamline 24-ID)]; U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]. Funding for open access charge: Howard Hughes Medical Institute.
Publisher Copyright:
© 2016 The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.
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.
UR - http://www.scopus.com/inward/record.url?scp=84963829763&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84963829763&partnerID=8YFLogxK
U2 - 10.1093/nar/gkw018
DO - 10.1093/nar/gkw018
M3 - Article
C2 - 26809677
AN - SCOPUS:84963829763
VL - 44
SP - 2439
EP - 2450
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 5
ER -