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.
Interactions between the extracellular matrix and membrane proteins are of importance for cell adhesion, tissue formation, and transmembrane signaling processes. Among cell adhesion molecules, integrins occupy a highly prominent position. Many integrins, among them a 5 b 1 and a V b 3 , recognize the tripeptide sequence -Arg-Gly-Asp-(RGD) in their ligands. The discovery of the role of the RGD sequence in cell-cell and cell-matrix interactions prompted the development of a broad variety of RGD peptides and peptidomimetics for potential therapeutic applications. Soluble derivatives of these compounds are able to competitively inhibit the interaction between an RGD-containing protein and its integrin counterpart, whereas immobilized RGD peptides support cell attachment, for example, to artificial implants.
The closely related neuropeptides orexin A and orexin B mediate their actions, including the regulation of sleep and appetite, by the activation of the orexin 1 and 2 receptors. To elucidate the structural prerequisites for receptor activation and subtype selectivity, we performed multiple amino acid substitutions within the sequence of orexin A and human orexin B-(6-28)-peptide and analyzed their solution structures by CD spectroscopy and their activity at both receptors in Ca(2+) mobilization assays. For orexin A, we showed that the basic amino acids within the segment of residues 6-14 were important for the activation of both receptors. Furthermore, we showed that the restriction via disulfide bonds is not required to maintain the active structure of orexin A. The kink region of h orexin B has been shown to be important for Ox(2)R selectivity, which is not mediated by the restriction of the turn structure. Additionally, we showed that no particular secondary structure is required for receptor subtype selectivity.
Sieben Aminosäuren genügen, damit acyclische α‐β‐Peptide (siehe Struktur) bei alternierender Kombination von L‐Alanin und cis‐β‐Aminocyclopropancarbonsäuren (cis‐β‐ACCs) stabile 313‐Helixschleifen in Lösung bilden. Entscheidend für die helicale Struktur dieser neuen Klasse von Foldameren ist die Konfiguration der cis‐β‐ACCs.
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