Surprisingly Stable Helical Conformations in α/β‐Peptides by Incorporation of <i>cis</i>‐β‐Aminocyclopropane Carboxylic Acids

Pol, Silvia De; Zorn, Chiara; Klein, Christian D.; Zerbe, Oliver; Reiser, Oliver

doi:10.1002/anie.200352267

Cited by 207 publications

(90 citation statements)

References 32 publications

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“…Such efforts have included the study of RNA analogues based on pyranose rather than furanose (3), peptides based on ␤-or ␥-amino acids rather than ␣-amino acids (4,5), and systems that diverge more profoundly from biological precedents (6,7). As the folding propensities of new backbone elements have been elucidated, the first steps have been taken to blend natural and unnatural subunits and thereby create folded oligomers with heterogeneous backbones and distinctive behavior (8)(9)(10).…”

mentioning

confidence: 99%

Interplay among side chain sequence, backbone composition, and residue rigidification in polypeptide folding and assembly

Horne

Price

Gellman

2008

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

113

151

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The extent to which polypeptide conformation depends on side-chain composition and sequence has been widely studied, but less is known about the importance of maintaining an α-amino acid backbone. Here, we examine a series of peptides with backbones that feature different repeating patterns of α- and β-amino acid residues but an invariant side-chain sequence. In the pure α-backbone, this sequence corresponds to the previously studied peptide GCN4-pLI, which forms a very stable four-helix bundle quaternary structure. Physical characterization in solution and crystallographic structure determination show that a variety of α/β-peptide backbones can adopt sequence-encoded quaternary structures similar to that of the α prototype. There is a loss in helix bundle stability upon β-residue incorporation; however, stability of the quaternary structure is not a simple function of β-residue content. We find that cyclically constrained β-amino acid residues can stabilize the folds of α/β-peptide GCN4-pLI analogues and restore quaternary structure formation to backbones that are predominantly unfolded in the absence of cyclic residues. Our results show a surprising degree of plasticity in terms of the backbone compositions that can manifest the structural information encoded in a sequence of amino acid side chains. These findings offer a framework for the design of nonnatural oligomers that mimic the structural and functional properties of proteins.

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mentioning

confidence: 99%

Interplay among side chain sequence, backbone composition, and residue rigidification in polypeptide folding and assembly

Horne

Price

Gellman

2008

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

113

151

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“…[25][26][27] In contrast to these investigations, the absolute configuration of the -ACC moiety had no influence on binding affinity of all analogues (9)(10)(11)(12)(13)(14)(15)(16). The 11-mer hRCGRP analogues (9-12) are devoid of any CGRP receptor binding (K i > 10 000 nM).…”

Section: Peptide Synthesis All Peptides (Shown Inmentioning

confidence: 88%

Identification of the Key Residue of Calcitonin Gene Related Peptide (CGRP) 27−37 to Obtain Antagonists with Picomolar Affinity at the CGRP Receptor

et al. 2005

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Calcitonin gene related peptide (CGRP) plays an important role in the CNS and in the cardiovascular system. To identify high-affinity antagonists in competitive binding studies, we identified a novel radioactive tracer, [(3)H-propionyl-K(24)]-halphaCGRP 8-37, which was labeled in solution by a recently developed strategy using photolabile protecting groups at reactive side chains. This tracer was shown to be as potent as commercially available (125)I-tracers for the determination of agonists and to have increased sensitivity for antagonists. We applied it to investigate the predicted turn structures centered at Pro(29) and Pro(34). The substitution at positions 29 and 34 by turn-inducing amino acid mimetica showed that these turns are highly diverse. At position 29, a hydrophobic residue is preferred that constricts the secondary structure, whereas position 34 is required to stabilize the conformation of the backbone. All high-affinity analogues showed antagonistic properties with potency similar to CGRP 8-37.

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“…[264–266] Thus, α/β-peptides were developed to improve the mimicry of an α-helix while ensuring enhanced resistance to proteolysis. [267] α-Amino acids are used for surface recognition, while the β-amino acids (mainly rigid cyclic β-amino acids and β 3 -Glu-β 3 -Lys pairs to form intramolecular salt bridges) are incorporated to support the helical conformation.…”

Section: Methodsmentioning

confidence: 99%

Structure‐Based Design of Inhibitors of Protein–Protein Interactions: Mimicking Peptide Binding Epitopes

et al. 2015

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Protein–protein interactions (PPIs) are involved at all levels of cellular organization, thus making the development of PPI inhibitors extremely valuable. The identification of selective inhibitors is challenging because of the shallow and extended nature of PPI interfaces. Inhibitors can be obtained by mimicking peptide binding epitopes in their bioactive conformation. For this purpose, several strategies have been evolved to enable a projection of side chain functionalities in analogy to peptide secondary structures, thereby yielding molecules that are generally referred to as peptidomimetics. Herein, we introduce a new classification of peptidomimetics (classes A–D) that enables a clear assignment of available approaches. Based on this classification, the Review summarizes strategies that have been applied for the structure-based design of PPI inhibitors through stabilizing or mimicking turns, β-sheets, and helices.

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Surprisingly Stable Helical Conformations in α/β‐Peptides by Incorporation of cis‐β‐Aminocyclopropane Carboxylic Acids

Cited by 207 publications

References 32 publications

Interplay among side chain sequence, backbone composition, and residue rigidification in polypeptide folding and assembly

Interplay among side chain sequence, backbone composition, and residue rigidification in polypeptide folding and assembly

Identification of the Key Residue of Calcitonin Gene Related Peptide (CGRP) 27−37 to Obtain Antagonists with Picomolar Affinity at the CGRP Receptor

Structure‐Based Design of Inhibitors of Protein–Protein Interactions: Mimicking Peptide Binding Epitopes

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