Crystal structure of a hydrophobic 19-residue peptide helix containing three centrally located
            <scp>d</scp>
            amino acids

Karle, Isabella L.; Gopi, Hosahudya N.; Balaram, Padmanabhan

doi:10.1073/pnas.2336106100

Cited by 40 publications

(32 citation statements)

References 28 publications

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“…This suggests that the hydrophobic environment of the surroundings can facilitate a "wild type"-like ␤-sheet structure. This is comparable with a recent report showing a similar structure of an ␣-helical peptide and its diastereomer (52,53). Deconvolution of the spectra revealed some differences in ␤-structure contributions between the FP and its IFFA diastereomer.…”

Section: Discussionsupporting

confidence: 90%

Inhibition of HIV-1 Envelope Glycoprotein-mediated Cell Fusion by a DL-Amino Acid-containing Fusion Peptide

Gerber

Pritsker

Günther-Ausborn

et al. 2004

Journal of Biological Chemistry

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The N-terminal fusion peptide (FP) of human immunodeficiency virus-1 (HIV-1) is a potent inhibitor of cellcell fusion, possibly because of its ability to recognize the corresponding segments inside the fusion complex within the membrane. Here we show that a fusion peptide in which the highly conserved Ile 4 , Phe 8 , Phe 11 , and Ala 14 were replaced by their D-enantiomers (IFFA) is a potent inhibitor of cell-cell fusion. Fourier transform infrared spectroscopy confirmed that despite these drastic modifications, the peptide preserved most of its structure within the membrane. Fluorescence energy transfer studies demonstrated that the diastereomeric peptide interacted with the wild type FP, suggesting this segment as the target site for inhibition of membrane fusion. This is further supported by the similar localization of the wild type and IFFA FPs to microdomains in T cells and the preferred partitioning into ordered regions within sphingomyelin/phosphatidyl-choline/cholesterol giant vesicles. These studies provide insight into the mechanism of molecular recognition within the membrane milieu and may serve in designing novel HIV entry inhibitors.Specific fusion proteins, located on the surface of viral membranes, mediate membrane fusion (1). The envelope glycoprotein gp160 from HIV, 1 containing two non-covalently associated subunits, gp120 and gp41 (2), mediates the membrane fusion activity of the virus. The binding of the gp120 subunit to target cell receptors (3-7) induces a conformational change in the glycoprotein, which results in the exposure of a previously hidden hydrophobic N-terminal stretch of gp41, designated the "fusion peptide" (8, 9). Evidence supporting the role of the FP domain in mediating membrane fusion came from studies with intact envelope proteins (10 -12), as well as synthetic peptides used in model and biological systems (13-25). However, the molecular mechanism of membrane fusion is still poorly understood despite extensive studies done in both biological and model systems. Nevertheless, the results of many studies suggest common motifs for the diverse biological and model fusion reactions (13,26).Virus-induced membrane fusion is highly sensitive to single amino acid mutations in the FP domain (27,28). This can lead to the conclusion that the structure of FPs is a crucial parameter in the fusion process. Indeed, several studies suggest that the structure of FPs plays a major role in their activities (12,29). To distinguish between the effects of structure and hydrophobicity, we compared an all-L-amino acid FP with its enantiomer composed entirely of D-amino acids (25). Both had the same activity in liposome fusion assays, although having mirror image structures (25). Furthermore, the FP of HIV-1 was shown to inhibit cell-cell fusion (30 -32). Cumulative evidence suggests that the mechanism of inhibition is through interaction with the corresponding region in the intact gp41 (23,25). This inhibitory activity of the peptide is chirality-independent, eliminating the possibility of intera...

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Section: Discussionsupporting

confidence: 90%

Inhibition of HIV-1 Envelope Glycoprotein-mediated Cell Fusion by a DL-Amino Acid-containing Fusion Peptide

Gerber

Pritsker

Günther-Ausborn

et al. 2004

Journal of Biological Chemistry

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“…The CD spectrum of the apopeptides confirmed that these constructs were well folded coiled coils. Although up to three D-amino acid substitutions in a 19-aa ␣-helix has been reported to be tolerated (27), this is a previously unreported example of D-amino acids substitutions in the interior of an otherwise all L-amino acid coiled coil construct.…”

Section: Discussionmentioning

confidence: 77%

“…Modifications can vary from single mutations that may be used to introduce hairpin turns or terminate ␣-helixes (22,23) or inversion of all amino acids to yield a mirror image structure (24,25). Single, double, and even triple D-amino acid substituted ␣-helixes have been investigated and found to be tolerated (26)(27)(28), and heteromeric coiled coils containing both left-and right-handed helixes made up of D-and L-amino acid building blocks, respectively, have been prepared (29). A major benefit of D-amino acids containing peptides is that they possess enhanced proteolytic stability, which has significant implications for therapeutic applications (30).…”

mentioning

confidence: 99%

Using diastereopeptides to control metal ion coordination in proteins

Peacock

Hemmingsen

Pecoraro

2008

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

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Here, we report a previously undescribed approach for controlling metal ion coordination geometry in biomolecules by reorientating amino acid side chains through substitution of L-to D-amino acids. These diastereopeptides allow us to manipulate the spatial orientation of amino acid side chains to alter the sterics of metal binding pockets. We have used this approach to design the de novo metallopeptide, Cd (TRIL12L DL16C)

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“…is the first high-resolution crystal structure of a protein containing a D-amino acid stabilized turn, extending crystallographic studies of D-amino acidcontaining peptides 51 to a globular domain. The structure verifies that D-Ala20 is well accommodated within the native fold; the resolution of the analysis has permitted similarities in solvation and thermal B factors to be assessed.…”

Section: Discussionmentioning

confidence: 94%

Diabetes Mellitus due to Misfolding of a β-Cell Transcription Factor: Stereospecific Frustration of a Schellman Motif in HNF-1α

Narayana

Phillips

Hua

et al. 2006

Journal of Molecular Biology

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Crystal structure of a hydrophobic 19-residue peptide helix containing three centrally located d amino acids

Cited by 40 publications

References 28 publications

Inhibition of HIV-1 Envelope Glycoprotein-mediated Cell Fusion by a DL-Amino Acid-containing Fusion Peptide

Inhibition of HIV-1 Envelope Glycoprotein-mediated Cell Fusion by a DL-Amino Acid-containing Fusion Peptide

Using diastereopeptides to control metal ion coordination in proteins

Diabetes Mellitus due to Misfolding of a β-Cell Transcription Factor: Stereospecific Frustration of a Schellman Motif in HNF-1α

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