Amide‐to‐Ester Substitution in Coiled Coils: The Effect of Removing Hydrogen Bonds on Protein Structure

Scheike, Jessica A.; Baldauf, Carsten; Spengler, Jan; Alberício, Fernando; Pisabarro, M. Teresa; Koksch, Beate

doi:10.1002/anie.200702218

Cited by 42 publications

(35 citation statements)

References 26 publications

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“…Although the correlation between V7v and G8g is 1 the correlation between G8g and V9v shows a strong anti-correlation of −0.53. A similar amino acid context-dependence has been found in solution for other depsipeptides [2,3,22]. This further supports the suggestion that these ETD observations are largely structural-dependent.…”

Section: Resultssupporting

confidence: 86%

Electron Transfer Dissociation Reveals Changes in the Cleavage Frequencies of Backbone Bonds Distant to Amide-to-Ester Substitutions in Polypeptides

Hansen

Jung

Kjeldsen

2011

J. Am. Soc. Mass Spectrom.

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Interrogation of electron transfer dissociation (ETD) mass spectra of peptide amide-to-ester backbone bond substituted analogues (depsipeptides) reveals substantial differences in the entire backbone cleavage frequencies. It is suggested that the point permutation of backbone bonds leads to changes in the predominant ion structures by removal/weakening of specific hydrogen bonding. ETD responds to these changes by redistributing the cleavage frequencies of the peptide backbone bonds. In comparison, no distinction between depsi-/peptide was observed using collision-activated dissociation, which is consistent with a general unfolding and elimination of structural information of these ions. These results should encourage further exploration of depsipeptides for gas-phase structural characterization.

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Section: Resultssupporting

confidence: 86%

Electron Transfer Dissociation Reveals Changes in the Cleavage Frequencies of Backbone Bonds Distant to Amide-to-Ester Substitutions in Polypeptides

Hansen

Jung

Kjeldsen

2011

J. Am. Soc. Mass Spectrom.

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“…In solvated positions, however, hydrogen bonding is expected to play a minor role. [41] Because the galactose residues are incorporated into the solvent-exposed face of the coiled-coil helices, hydrogen bonding to the peptide backbone will have a negligible effect on this particular conformation. However, in the hydrophobic environment of b-sheets, sugar competition for intermolecular hydrogen bonds will have a distinct destabilizing effect on the overall integrity of this structure.…”

Section: Discussionmentioning

confidence: 99%

“…[11,19,20] We have explored the a-helical coiled coil folding motif, which is very common in nature and has been extensively studied in recent years, proving its application as a reliable model system. [9,11,19,20,41] Furthermore, the design principles of coiled coils are very well understood, [21] and folding is based on oligomerization, which is also the foundation of amyloid formation. Coiled coils consist of at least two a-helices wrapped around each other in a slight superhelical twist.…”

Section: Introductionmentioning

confidence: 99%

How Post‐Translational Modifications Influence Amyloid Formation: A Systematic Study of Phosphorylation and Glycosylation in Model Peptides

Broncel

Falenski

Wagner

et al. 2010

Chemistry A European J

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A reciprocal relationship between phosphorylation and O-glycosylation has been reported for many cellular processes and human diseases. The accumulated evidence points to the significant role these post-translational modifications play in aggregation and fibril formation. Simplified peptide model systems provide a means for investigating the molecular changes associated with protein aggregation. In this study, by using an amyloid-forming model peptide, we show that phosphorylation and glycosylation can affect folding and aggregation kinetics differently. Incorporation of phosphoserines, regardless of their quantity and position, turned out to be most efficient in preventing amyloid formation, whereas O-glycosylation has a more subtle effect. The introduction of a single beta-galactose does not change the folding behavior of the model peptide, but does alter the aggregation kinetics in a site-specific manner. The presence of multiple galactose residues has an effect similar to that of phosphorylation.

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“…[36, 71–73] In general, replacement of a hydrogen-donating NH-group by the oxygen atom in depsipeptides results in removal of the backbone H-bond, affecting therefore conformation of peptides. As long as the side chains are not altered, intramolecular hydrogen bonds affect the equilibrium distribution of peptide conformers.…”

Section: Discussionmentioning

confidence: 99%

Effects of Cyclic Lipodepsipeptide Structural Modulation on Stability, Antibacterial Activity, and Human Cell Toxicity

et al. 2012

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Bacterial infections are becoming increasingly difficult to treat due to the development and spread of antibiotic resistance. Therefore, identifying novel antibacterial targets and new antibacterial agents capable of treating infections from drug-resistant bacteria is of vital importance. Structurally simple, yet potent fusaricidin or LI-F class of natural products represents a particularly attractive source of candidates for the development of new antibacterial agents. We have synthesized eighteen fusaricidin/LI-F analogs and investigated the effect of their structure modification on conformation, serum stability, antibacterial activity and human cell toxicity. Our findings show that substitution of an ester bond in depsipeptides with an amide bond may afford equally potent analogs with improved stability and greatly decreased cytotoxicity. Lower overall hydrophobicity/amphiphilicity of amide analogs in comparison to their parent depsipeptides, as indicated by the HPLC retention times, may explain dissociation of antibacterial activity and human cell cytotoxicity. These results indicate that amide analogs may have significant advantages over fusaricidin/LI-F natural products and their depsipeptide analogs as lead structures for the development of new antibacterial agents.

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Amide‐to‐Ester Substitution in Coiled Coils: The Effect of Removing Hydrogen Bonds on Protein Structure

Cited by 42 publications

References 26 publications

Electron Transfer Dissociation Reveals Changes in the Cleavage Frequencies of Backbone Bonds Distant to Amide-to-Ester Substitutions in Polypeptides

Electron Transfer Dissociation Reveals Changes in the Cleavage Frequencies of Backbone Bonds Distant to Amide-to-Ester Substitutions in Polypeptides

How Post‐Translational Modifications Influence Amyloid Formation: A Systematic Study of Phosphorylation and Glycosylation in Model Peptides

Effects of Cyclic Lipodepsipeptide Structural Modulation on Stability, Antibacterial Activity, and Human Cell Toxicity

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