Biological and physical properties of a model calcitonin containing a glutamate residue interrupting the hydrophobic face of the idealized amphiphilic alpha-helical region.
2A new calcitonin analogue, model calcitonin III (MCt-III), has been synthesized, and its biological and physical characteristics have been studied. This analogue has an idealized alpha-helix from residue 8-22 with glutamate at position 15 interrupting an otherwise continuous surface of aliphatic side chains (those of leucine residues) on the hydrophobic face of the helix. MCt-III differs from a previous model, MCt-II, only by the substitution Leu15----Glu and is here compared with salmon calcitonin I (sCt-I) and MCt-II to elucidate further the role of the putative amphiphilic alpha-helix in determining biological and physical properties of the hormone. MCt-III shows physical properties intermediate between those of sCt-I and MCt-II, demonstrating the influence of appropriately positioned single residues on properties of amphiphilic structures. In our two biological assays, a brain-binding assay and an in vivo hypocalcemic assay, MCt-III reproduces the sigmoidal dose-response curves of sCt-I; this contrasts with the behavior of MCt-II, which demonstrated unusual dose-response curves in these two assays. MCt-III is almost three times more potent than sCt-I in our hypocalcemic assay; this activity groups MCt-III among the most potent known analogues of sCt-I.
Green
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FR
Laboratory of Bioorganic Chemistry and Biochemistry, Rockefeller University, New York, NY 10021.
Lynch
B
B
Kaiser
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ET
D000818:Animals; D001681:Biological Assay; D001921:Brain / Q000378:metabolism; D002116:Calcitonin / Q000502:physiology*; D002942:Circular Dichroism; D005971:Glutamates; D008970:Molecular Weight; D011487:Protein Conformation; D051381:Rats; D018003:Receptors, Calcitonin; D011956:Receptors, Cell Surface / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D014461:Ultracentrifugation
D005971:Glutamates; D018003:Receptors, Calcitonin; D011956:Receptors, Cell Surface; D002116:Calcitonin