7zra
From Proteopedia
(Difference between revisions)
| Line 14: | Line 14: | ||
Antimicrobial resistance threatens the eradication of infectious diseases and impairs the efficacy of available therapeutics. The bacterial SOS pathway is a conserved response triggered by genotoxic stresses and represents one of the principal mechanisms that lead to resistance. The RecA recombinase acts as a DNA-damage sensor inducing the autoproteolysis of the transcriptional repressor LexA, thereby derepressing SOS genes that mediate DNA repair, survival to chemotherapy, and hypermutation. The inhibition of such pathway represents a promising strategy for delaying the evolution of antimicrobial resistance. We report the identification, via llama immunization and phage display, of nanobodies that bind LexA with sub-micromolar affinity and block autoproteolysis, repressing SOS response in Escherichia coli. Biophysical characterization of nanobody-LexA complexes revealed that they act by trapping LexA in an inactive conformation and interfering with RecA engagement. Our studies pave the way to the development of new-generation antibiotic adjuvants for the treatment of bacterial infections. | Antimicrobial resistance threatens the eradication of infectious diseases and impairs the efficacy of available therapeutics. The bacterial SOS pathway is a conserved response triggered by genotoxic stresses and represents one of the principal mechanisms that lead to resistance. The RecA recombinase acts as a DNA-damage sensor inducing the autoproteolysis of the transcriptional repressor LexA, thereby derepressing SOS genes that mediate DNA repair, survival to chemotherapy, and hypermutation. The inhibition of such pathway represents a promising strategy for delaying the evolution of antimicrobial resistance. We report the identification, via llama immunization and phage display, of nanobodies that bind LexA with sub-micromolar affinity and block autoproteolysis, repressing SOS response in Escherichia coli. Biophysical characterization of nanobody-LexA complexes revealed that they act by trapping LexA in an inactive conformation and interfering with RecA engagement. Our studies pave the way to the development of new-generation antibiotic adjuvants for the treatment of bacterial infections. | ||
| - | Nanobodies targeting LexA autocleavage disclose a novel suppression strategy of SOS-response pathway.,Maso L, Vascon F, Chinellato M, Goormaghtigh F, Bellio P, Campagnaro E, Van Melderen L, Ruzzene M, Pardon E, Angelini A, Celenza G, Steyaert J, Tondi D, Cendron L Structure. 2022 | + | Nanobodies targeting LexA autocleavage disclose a novel suppression strategy of SOS-response pathway.,Maso L, Vascon F, Chinellato M, Goormaghtigh F, Bellio P, Campagnaro E, Van Melderen L, Ruzzene M, Pardon E, Angelini A, Celenza G, Steyaert J, Tondi D, Cendron L Structure. 2022 Nov 3;30(11):1479-1493.e9. doi: 10.1016/j.str.2022.09.004. Epub , 2022 Oct 13. PMID:36240773<ref>PMID:36240773</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
Crystal structure of E.coli LexA in complex with nanobody NbSOS1(Nb14497)
| |||||||||||
Categories: Escherichia coli | Lama glama | Large Structures | Angelini A | Cendron L | Chinellato M | Maso L | Pardon E | Steyaert J | Tondi D | Vascon F
