Structural determinants of salmon calcitonin bioactivity: the role of the Leu-based amphipathic a-helix (Articolo in rivista)

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Label
  • Structural determinants of salmon calcitonin bioactivity: the role of the Leu-based amphipathic a-helix (Articolo in rivista) (literal)
Anno
  • 2006-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1074/jbc.M603528200 (literal)
Alternative label
  • Andreotti G.; López Méndez B.; Amodeo P.; Castiglione Morelli M. A.; Nakamuta H.; Motta A.; (2006)
    Structural determinants of salmon calcitonin bioactivity: the role of the Leu-based amphipathic a-helix
    in The Journal of biological chemistry (Print)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Andreotti G.; López Méndez B.; Amodeo P.; Castiglione Morelli M. A.; Nakamuta H.; Motta A.; (literal)
Pagina inizio
  • 24193 (literal)
Pagina fine
  • 24203 (literal)
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  • 281 (literal)
Rivista
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo
  • 34 (literal)
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  • Caratterizzazione dei dettagli strutturali che regolano l'attività della calcitonina, un ormone largamente utilizzato nella cura dell'osteoporosi e dell'ipercalcemia. Possibilità di progettare analoghi con attività farmacologica elevata ma senza effetti collaterali. (literal)
Note
  • Scopu (literal)
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Istituto di Chimica Biomolecolare del Consiglio Nazionale delle Ricerche, Comprensorio Olivetti, Edificio A, 80078 Pozzuoli (Napoli), Italy; Dipartimento di Chimica, Università della Basilicata, 85100 Potenza, Italy; Laboratory of Pharmacology, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Hiroshima International University, Hirokoshingai 5-1-1, Kure, Hiroshima 737-0112, Japan. (literal)
Titolo
  • Structural determinants of salmon calcitonin bioactivity: the role of the Leu-based amphipathic a-helix (literal)
Abstract
  • Salmon calcitonin (sCT) forms an amphipathic helix in the region 9-19, with the C-terminal decapeptide interacting with the helix (Amodeo, P., Motta, A., Strazzullo, G., Castiglione Morelli, M. A. (1999) J. Biomol. NMR 13, 161-174). To uncover the structural requirementsforthehormonebioactivity,weinvestigatedseveralsCT analogs. They were designed so as to alter the length of the central helixbyremovaland/orreplacementofflankingresiduesandbyselectively mutating or deleting residues inside the helix.Thehelix content was assessed by circular dichroism and NMR spectroscopies; the receptor binding affinity in human breast cancer cell line T 47D and the in vivo hypocalcemic activity were also evaluated. In particular, by NMR spectroscopy and molecular dynamics calculations we studied Leu23,Ala24-sCT in which Pro23 and Arg24 were replaced by helix inducing residues. Compared with sCT, it assumes a longer amphipathic?-helix, with decreased binding affinity and one-fifth of the hypocalcemic activity, therefore supporting the idea of a relationship between a definite helix length and bioactivity. From the analysis of other sCT mutants, we inferred that the correct helix length is located in the 9-19 region and requires long range interactions and the presence of specific regions of residues within the sequence for high binding affinity and hypocalcemic activity. Taken together, the structural and biological data identify well defined structural parameters of the helix for sCT bioactivity. (literal)
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