Substitution of the GalNAc-α-O-Thr11 residue in drosocin with O-linked glyco-peptoid residue: Effect on antibacterial activity and conformational change

Ahn, Mok-Ryeon; Murugan, Ravichandran N.; Nan, Yong Hai; Cheong, Chaejoon; Sohn, Hoik; Kim, Eun‐Hee; Hwang, Eunha; Ryu, Eung K.; Kang, Shin Won; Shin, Song Yub; Bang, Jeong Kyu

doi:10.1016/j.bmcl.2011.08.012

Cited by 12 publications

(3 citation statements)

References 11 publications

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“…This interaction rationalizes our ( Fig. 1 ), and previous (Ahn et al, 2011a; Ahn et al, 2011b; Gobbo et al, 2002; Lele et al, 2015a; Marcaurelle et al, 1998; Otvos et al, 2000; Rodriguez et al, 1997; Talat et al, 2011) observations that the native modified forms of drosocin generally display enhanced antimicrobial activity compared to the unmodified peptide. Interestingly, we observe drosocin causes a shift of U2609 that breaks the base-pair that U2609 usually forms with A752 ( Fig.…”

Section: Discussionsupporting

confidence: 91%

“…Synthetic drosocin lacking O-glycosylation is less active than the native compounds, suggesting that the post-translational modification is necessary for full activity (Bulet et al, 1993; Bulet et al, 1999; Bulet et al, 1996; Gobbo et al, 2002; Hoffmann et al, 1999). Indeed, many studies have demonstrated that a variety of synthetic drosocin derivatives with varying sugar moieties maintain good antimicrobial activity, generally better than the unmodified form (Ahn et al, 2011a; Ahn et al, 2011b; Gobbo et al, 2002; Lele et al, 2015a; Marcaurelle et al, 1998; Otvos et al, 2000; Rodriguez et al, 1997; Talat et al, 2011). Although NMR and CD experiments suggest that both the modified and unmodified forms of drosocin adopt extended conformations in solution (Bulet et al, 1996; Gobbo et al, 2002; Lele et al, 2015a; McManus et al, 1999; Talat et al, 2011), the presence of the modification has nevertheless been proposed to help drosocin maintain an extended conformation to facilitate binding to its intracellular target (Bulet et al, 1999; Gobbo et al, 2002; McManus et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Structural basis for translation inhibition by the glycosylated antimicrobial peptide Drosocin fromDrosophila melanogaster

Koller

Morici

Berger

et al. 2022

Preprint

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The proline-rich antimicrobial peptide (PrAMP) drosocin is produced by Drosophila species to combat bacterial infection. Unlike many PrAMPs, drosocin is O-glycosylated at threonine 11, a post-translation modification that enhances its antimicrobial activity. Here we demonstrate that the O-glycosylation influences not only cellular uptake of the peptide, but also interacts with its intracellular target, the ribosome. Cryo-electron microscopy structures of glycosylated drosocin on the ribosome at 2.1-2.8 A resolution reveal that the peptide interferes with translation termination by binding within the polypeptide exit tunnel and trapping RF1 on the ribosome, reminiscent of that reported for the PrAMP apidaecin. The glycosylation of drosocin enables multiple interactions with U2609 of the 23S rRNA, leading to conformational changes that break the canonical base-pair with A752. Collectively, our study provides novel molecular insights into the interaction of O-glycosylated drosocin with the ribosome, which provides a structural basis for future development of this class of antimicrobials.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Structural basis for translation inhibition by the glycosylated antimicrobial peptide Drosocin fromDrosophila melanogaster

Koller

Morici

Berger

et al. 2022

Preprint

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“…Previous efforts to improve the antibiotic activity of Dro involved introduction of specific amino acid changes in its structure 33,45,46 . Some of these alterations indeed yielded derivatives with somewhat improved antibacterial properties or serum stability 45,[47][48][49] . However, labor-and time-consuming peptide synthesis limits the systematic evaluation of the contribution of the PrAMPs residues for activity.…”

Section: Endogenously Expressed Dro Retains Its Mechanism Of Action A...mentioning

confidence: 99%

Inhibition of translation termination by Drosocin, an antimicrobial peptide from fruit flies

Mangano

Klepacki

Ohanmu

et al. 2022

Preprint

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A 19-amino acid long proline-rich antimicrobial peptide (PrAMP) Drosocin (Dro) is encoded in the fruit fly genome. Native Dro is glycosylated at a specific threonine residue, but the non-glycosylated peptide retains antibacterial activity. Dro shows sequence similarity to several other PrAMPs that bind in the ribosomal nascent peptide exit tunnel and inhibit protein synthesis by varying mechanisms. However, the target and mechanism of action of Dro remain unknown. Here we show that the primary mode of Dro action is inhibition of termination of protein synthesis. Our in vitro and in vivo experiments demonstrate that Dro stalls ribosomes at stop codons, likely sequestering class 1 release factors associated with the terminating ribosome. As the result, Dro, at subinhibitory concentrations, strongly promotes readthrough of stop codons. The elucidated mode of Dro action allows assigning it as the second member of the type II PrAMPs, of which only one representative, the antimicrobial peptide apidaecin (Api) produced by honeybees, was previously known. However, despite its functional similarity with Api, Dro interacts with the target in a markedly distinct way. The analysis of a comprehensive single-amino acid substitution library of endogenously expressed Dro variants shows that binding to the ribosome involves interactions of multiple amino acid residues distributed through the entire length of the PrAMP. Our data further show that the ribosome-targeting activity of non-glycosylated Dro can be significantly enhanced by single amino acid substitutions illuminating directions for improving its antibacterial properties.

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From Glycopeptides to Glycopeptoids

Szekely¹,

Roy²,

Faure³

et al. 2014

Eur J Org Chem

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This review covers the published literature describing the synthesis of glycopeptoids, a family of glycopeptide mimics. Members of this family are composed of an N‐substituted glycine or β‐alanine oligomer backbone linked to one or several carbohydrate moieties at the amide nitrogen atoms. The interest in this class of biomimetics lies in their enhanced proteolytic stability and greater conformational flexibility relative to glycopeptides. This Microreview not only describes the different methods for synthesising glycopeptoids but also discusses their application both as glycopeptidomimetics and glycocluster constructs.

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Substitution of the GalNAc-α-O-Thr11 residue in drosocin with O-linked glyco-peptoid residue: Effect on antibacterial activity and conformational change

Cited by 12 publications

References 11 publications

Structural basis for translation inhibition by the glycosylated antimicrobial peptide Drosocin fromDrosophila melanogaster

Structural basis for translation inhibition by the glycosylated antimicrobial peptide Drosocin fromDrosophila melanogaster

Inhibition of translation termination by Drosocin, an antimicrobial peptide from fruit flies

From Glycopeptides to Glycopeptoids

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