Identification of
            <scp>d</scp>
            -Peptide Ligands Through Mirror-Image Phage Display

Schumacher, Ton N.; Mayr, Lorenz M.; Minor, Daniel L.; Milhollen, Michael A.; Burgess, Michael; Kim, Peter

doi:10.1126/science.271.5257.1854

Cited by 355 publications

(283 citation statements)

References 47 publications

Supporting

Mentioning

278

Contrasting

Unclassified

Order By: Relevance

“…One of the Dpeptides showed detectable binding even though it was very poor. Similar to these results, the identi®cation of low a nity D-amino acid binding peptides for the Src SH3 domain by mirror image phage display has been reported previously (Schumacher et al, 1996).…”

Section: Resultssupporting

confidence: 87%

Development of highly selective SH3 binding peptides for Crk and CRKL which disrupt Crk-complexes with DOCK180, SoS and C3G

Posern¹,

Zheng

Knudsen

et al. 1998

Oncogene

View full text Add to dashboard Cite

Many Src Homology 3 (SH3) domains function as molecular adhesives in intracellular signal transduction. Based on previous ultrastructural studies, short motifs which bind to the ®rst SH3 domains of the adapters Crk and CRKL were selectively mutagenised to generate Crk/ CRKL SH3-binding peptides of very high a nity and selectivity. A nities were increased up to 20-fold compared to the best wildtype sequences, while the selectivity against a similar SH3 domain [Grb2SH3(N)] was not only retained, but sometimes increased. Blot techniques with GST-fusion peptides and in solution precipitation assays with biotinylated high a nity Crk binding peptides (HACBPs) were subsequently used to analyse the binding of these sequences to a large panel of SH3 domain-containing fusion proteins. Only those proteins which contained the CrkSH3(1) or CRKLSH3(1) domains bound e ciently to the HACBPs. A GST-HACBP fusion protein precipitated Crk and CRKL proteins out of 35 S-labelled and unlabelled cell lysates. Very little binding of other cellular proteins to HACBP was detectable, indicative of a great preference for Crk and CRKL when compared to the wide variety of other endogenous cellular proteins. Moreover, HACBP disrupted in vitro preexisting Crk-complexes with DOCK180 and the exchange factors SoS and C3G, which are known targets of Crk adapters, in a concentration dependent manner. HACBP-based molecules should therefore be useful as highly selective inhibitors of intracellular signalling processes involving Crk and CRKL.

show abstract

Section: Resultssupporting

confidence: 87%

Development of highly selective SH3 binding peptides for Crk and CRKL which disrupt Crk-complexes with DOCK180, SoS and C3G

Posern¹,

Zheng

Knudsen

et al. 1998

Oncogene

View full text Add to dashboard Cite

show abstract

“…An approach similar to this has recently been used to identify an all-D-amino acid opioid peptide with analgesic activity capable of crossing the blood brain barrier using a synthetic combinatorial library made up of D-amino acid hexapeptides (59). In addition, the identification of D-peptide ligands through mirror image phage display using genetically encoded libraries (60) offers the promise of rapidly screening for D-peptide ligands that can block assembly and or neurotoxicity of the A␤ peptide. All-D-ligands are generally resistant to proteolysis and D-amino acid proteins are reported to have low immunogenicity, thus making them useful for pharmacological applications (61).…”

Section: Discussionmentioning

confidence: 99%

All-D-Enantiomers of β-Amyloid Exhibit Similar Biological Properties to All-L-β-Amyloids

Cribbs

Pike²,

Weinstein³

et al. 1997

Journal of Biological Chemistry

View full text Add to dashboard Cite

The amyloidogenic peptide ␤-amyloid has previously been shown to bind to neurons in the form of fibrillar clusters on the cell surface, which induces neurodegeneration and activates a program of cell death characteristic of apoptosis. To further investigate the mechanism of A␤ neurotoxicity, we synthesized the all-D-and all-Lstereoisomers of the neurotoxic truncated form of A␤ (A␤ [25][26][27][28][29][30][31][32][33][34][35] ) and the full-length peptide (A␤ 1-42 ) and compared their physical and biological properties. We report that the purified peptides exhibit nearly identical structural and assembly characteristics as assessed by high performance liquid chromatography, electron microscopy, circular dichroism, and sedimentation analysis. In addition, both enantiomers induce similar levels of toxicity in cultured hippocampal neurons. These data suggest that the neurotoxic actions of A␤ result not from stereoisomer-specific ligand-receptor interactions but rather from A␤ cellular interactions in which fibril features of the amyloidogenic peptide are a critical feature. The promiscuous nature of these ␤-sheet-containing fibrils suggests that the accumulation of amyloidogenic peptides in vivo as extracellular deposits represents a site of bioactive peptides with the ability to provide inappropriate signals to cells leading to cellular degeneration and disease.Alzheimer's disease (AD), 1 vascular dementia, and hereditary cerebral hemorrhage with the Dutch type are diseases that share an invariant pathological feature, the accumulation of an amyloidogenic peptide into insoluble fibrillar extracellular deposits. In all three cases, the major component of the extracellular debris is the ␤-amyloid peptide (A␤) that is derived from the proteolytic processing of the large membraneanchored amyloid precursor protein (APP) encoded by a single gene located on chromosome 21 (1). However, the biological significance of these amyloid deposits has been extensively debated as to whether they are a causative factor of each disease or merely a metabolically inert end product lacking in biological activity. Evidence in support of a causative role for A␤ in neuropathology comes from genetic analysis of the APP gene where several autosomal dominant mutations have been linked with AD and hereditary cerebral hemorrhage with the Dutch type (2, 3). In a recent in vitro study, the ␤-APP 717 mutation consistently caused a significant increase in the percentage of the longer and more amyloidogenic A␤ 1-42 over the shorter A␤ 1-40 (4). Incorporation of this same mutation into a transgenic mouse model yields A␤ deposition and neuropathology that closely parallels that observed in AD (5). Additional in vivo evidence suggesting that the A␤ peptide itself may be biologically active comes from a transgenic model overexpressing A␤ , in which A␤ transgene expression was detected in a variety of peripheral tissues but histopathological changes were restricted to the brain. Moreover, the neurodegeneration was largely limited to the cerebral cortex, ...

show abstract

“…"Mirror-image phage display," a powerful method pioneered by Kim and co-workers, has identified D peptides that bind tightly to L proteins (6). A few of these heterochiral complexes have been characterized at atomic resolution (7,8), but no general principles of heterochiral recognition have emerged.…”

mentioning

confidence: 99%

High-resolution structures of a heterochiral coiled coil

Mortenson

Steinkruger

Kreitler

et al. 2015

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

View full text Add to dashboard Cite

Interactions between polypeptide chains containing amino acid residues with opposite absolute configurations have long been a source of interest and speculation, but there is very little structural information for such heterochiral associations. The need to address this lacuna has grown in recent years because of increasing interest in the use of peptides generated from D amino acids (D peptides) as specific ligands for natural proteins, e.g., to inhibit deleterious proteinprotein interactions. Coiled-coil interactions, between or among α-helices, represent the most common tertiary and quaternary packing motif in proteins. Heterochiral coiled-coil interactions were predicted over 50 years ago by Crick, and limited experimental data obtained in solution suggest that such interactions can indeed occur. To address the dearth of atomic-level structural characterization of heterochiral helix pairings, we report two independent crystal structures that elucidate coiled-coil packing between L-and D-peptide helices. Both structures resulted from racemic crystallization of a peptide corresponding to the transmembrane segment of the influenza M2 protein. Networks of canonical knobs-into-holes side-chain packing interactions are observed at each helical interface. However, the underlying patterns for these heterochiral coiled coils seem to deviate from the heptad sequence repeat that is characteristic of most homochiral analogs, with an apparent preference for a hendecad repeat pattern.D peptides | transmembrane peptides | racemic crystallization | racemic detergent | coiled coil P olypeptides comprising D-amino acid residues have been sources of growing interest for biological applications, often for functions that depend on recognition by specific natural proteins (1-3). D peptides offer identical versatility in terms of conformation and side-chain functionality relative to conventional peptides (composed of L-amino acid residues), but D peptides are impervious to the action of proteolytic enzymes, which should improve pharmacokinetic properties in vivo relative to those of conventional peptides. The engineering of D peptides to display defined protein-binding preferences is hindered, however, by the dearth of experimental information available for such complexes. Structural principles that are well-known to govern interactions between two L-polypeptide chains are not directly extensible to pairings between peptides of opposite chirality. Favorable heterochiral interactions (between L-and D peptides) that are analogous to homochiral associations between L peptides were postulated decades ago on the basis of geometrical considerations (4, 5). In a 1953 analysis of structural parameters governing coiled-coil formation between right-handed α-helices formed from L peptides, for example, Crick suggested that analogous assemblies should be accessible to pairs of right-and left-handed helices (4). In the same year, Pauling and Corey postulated that heterochiral peptide mixtures could form "rippled" β-sheet assemblies with backbo...

show abstract

Identification of d -Peptide Ligands Through Mirror-Image Phage Display

Cited by 355 publications

References 47 publications

Development of highly selective SH3 binding peptides for Crk and CRKL which disrupt Crk-complexes with DOCK180, SoS and C3G

Development of highly selective SH3 binding peptides for Crk and CRKL which disrupt Crk-complexes with DOCK180, SoS and C3G

All-D-Enantiomers of β-Amyloid Exhibit Similar Biological Properties to All-L-β-Amyloids

High-resolution structures of a heterochiral coiled coil

Contact Info

Product

Resources

About