Conformation and interactions of all-d-, retro-all-d- and retro-bombolitin III analogues in aqueous solution and in the presence of detergent micelles?

Bisello, Alessandro; Sala, S.; Tonello, Antonella; Signor, Giovanni; Melotto, Elisa; Mammi, Stefano; Peggion, Evaristo

doi:10.1016/0141-8130(95)98155-r

Cited by 7 publications

(5 citation statements)

References 15 publications

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“…A much less pronounced temperature factor gradient is observed in the native GCN4-p1 structure (6) and is entirely lacking in the tetrameric GCN4-pLI mutant (13). The increased rigidity in the central parts of the retro-peptide superhelix corresponds with the results that have been obtained in the retro-bombolitin III peptide entrapped in SDS micelles that has a central helical segment, as determined by NMR spectroscopy (20).…”

Section: Resultssupporting

confidence: 50%

The retro -GCN4 leucine zipper sequence forms a stable three-dimensional structure

Mittl

Deillon

Sargent

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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The question of whether a protein whose natural sequence is inverted adopts a stable fold is still under debate. We have determined the 2.1-Å crystal structure of the retro-GCN4 leucine zipper. In contrast to the two-stranded helical coiled-coil GCN4 leucine zipper, the retro-leucine zipper formed a very stable, parallel four-helix bundle, which now lends itself to further structural and functional studies. Since the early folding experiments by Anfinsen (1), it has been accepted that structure and function of a protein are determined by its amino acid sequence as read from the N terminus to the C terminus. But how does the structure change if the amino acid sequence of the protein is inverted? Inverted sequences are occasionally found in genomic DNA, but thus far, a native retro-protein has not been detected. Physicochemical properties that are related to the amino acid composition or the hydrophobicity profile should not be affected by the inversion of the sequence, supporting the idea that retro-sequences might fold into a native-like conformation. Modeling experiments suggested that reversal of the backbone direction may result in a topological mirror image of the native structure of the protein (2) or may produce the same topology as that of the parent protein (3, 4). Thus far, no structure elucidation of a retro-Lpeptide at atomic resolution has been reported.Coiled coils, including leucine zippers, consist of two to five intertwined ␣-helices and are frequently found in oligomeric proteins such as transcription factors as well as motility and structural proteins (5). We used the two-stranded coiled-coil domain of the yeast transcription activator GCN4 (6) to dimerize an artificial HIV enhancer-binding peptide, an operation that resulted in increased inhibition of HIV enhancer-controlled transcription (7). Because modeling studies suggested that the retro-sequence of the GCN4 leucine zipper also seemed to form a suitable dimerization module, a 35-residue retro-GCN4 was synthesized and characterized. Oxidized retro-leucine zipper extended with Cys-Gly-Gly, previously termed (r-LZ38) 2 (r-GCN4-p1Ј; Fig. 1A), crystallized and is now shown by x-ray structure analysis to fold into a parallel tetrameric coiled coil. Materials and MethodsUltracentrifugation. Sedimentation velocity experiments were performed with a Beckman-Spinco XL-A analytical ultracentrifuge. The peptide was dissolved in 20 mM Tris⅐HCl͞80 mM NaCl adjusted to pH 5.0, and measurements were made over a 10-to 100-M peptide concentration range. The centrifuge was operated at a speed of 50,000 rpm at 20°C. A partial specific volume, v 20 ϭ 0.74 cm 3 ⅐g Ϫ1, was calculated from the amino acid composition as was an estimate of the degree of hydration, d 1 ϭ 0.47 g water͞g protein. Sedimentation velocity traces were analyzed according to the method described in ref. 8, and a value of the sedimentation coefficient, s w,20 ϭ 1.77 Ϯ 0.5 Svedberg, was obtained by extrapolation to infinite dilution. The axial ratio was calculated as described in ref. 9.Crysta...

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Section: Resultssupporting

confidence: 50%

The retro -GCN4 leucine zipper sequence forms a stable three-dimensional structure

Mittl

Deillon

Sargent

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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“…Here, we describe the design of β-peptides that mimic the activities of a class of natural membrane-active peptide toxins and antibiotics, , which includes magainins, bombolitin, cecropins, melittin, and mastoparans. − The biological active conformation of these peptides has been shown to consist of a positively charged, amphiphilic α-helix (Figure ). These helices kill cells by disrupting the structural integrity of their phospholipid membranes. − The overall physicochemical properties of these helices, and not their precise sequences or chirality, , have been proposed to be the key features required for activity. Thus, it should be possible to design amphiphilic β-peptide-based toxins and antibiotics.…”

mentioning

confidence: 99%

“…These helices kill cells by disrupting the structural integrity of their phospholipid membranes. [10][11][12][13][14][15][16][17][18][19] The overall physicochemical properties of these helices, and not their precise sequences or chirality, 20,21 have been proposed to be the key features required for activity. Thus, it should be possible to design amphiphilic β-peptide-based toxins and antibiotics.…”

mentioning

confidence: 99%

De Novo Design of Antibacterial β-Peptides

1999

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“…Indeed, AMPs usually adopt facially amphiphilic conformations in which cationic hydrophilic and hydrophobic side chains segregate onto opposite regions of the molecular surface. The importance of this overall topology and not the precise sequence, secondary structure, or chirality of the peptides has been highlighted as key features for their cell-killing activity [34]. Seminal works from Seebach [11] and more recently from Balaram [13,35] suggest that achiral β 2,2 -amino acids are β-turn inducers.…”

Section: Discussionmentioning

confidence: 99%

Small AntiMicrobial Peptide with In Vivo Activity Against Sepsis

et al. 2019

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Antimicrobial peptides (AMPs) are considered as potential therapeutic sources of future antibiotics because of their broad-spectrum activities and alternative mechanisms of action compared to conventional antibiotics. Although AMPs present considerable advantages over conventional antibiotics, their clinical and commercial development still have some limitations, because of their potential toxicity, susceptibility to proteases, and high cost of production. To overcome these drawbacks, the use of peptides mimics is anticipated to avoid the proteolysis, while the identification of minimalist peptide sequences retaining antimicrobial activities could bring a solution for the cost issue. We describe here new polycationic -amino acids combining these two properties, that we used to design small dipeptides that appeared to be active against Gram-positive and Gram-negative bacteria, selective against prokaryotic versus mammalian cells, and highly stable in human plasma. Moreover, the in vivo data activity obtained in septic mice reveals that the bacterial killing effect allows the control of the infection and increases the survival rate of cecal ligature and puncture (CLP)-treated mice.

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Conformation and interactions of all-d-, retro-all-d- and retro-bombolitin III analogues in aqueous solution and in the presence of detergent micelles?

Cited by 7 publications

References 15 publications

The retro -GCN4 leucine zipper sequence forms a stable three-dimensional structure

The retro -GCN4 leucine zipper sequence forms a stable three-dimensional structure

De Novo Design of Antibacterial β-Peptides

Small AntiMicrobial Peptide with In Vivo Activity Against Sepsis

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