Conformational studies of TOAC-labeled bradykinin analogues in model membranes

Conformational studies of TOAC-labeled bradykinin analogues in model membranes

Autor Vieira, RFF Google Scholar
Casallanovo, F. Google Scholar
Cilli, E. M. Google Scholar
Paiva, ACM Google Scholar
Schreier, S. Google Scholar
Nakaie, C. R. Google Scholar
Instituição Universidade Federal de São Paulo (UNIFESP)
Universidade de São Paulo (USP)
Resumo Spin-labeled analogues of bradykinin (BK) were synthesized containing the amino acid TOAC ( 2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid) either before Arg(1) (TOAC(0)-BK) or replacing Pro(3) (TOAC(3)-BK). Whereas the latter is inactive, the former retains about 70% of BK's activity in isolated rat uterus. A combined electron paramagnetic resonance (EPR)-circular dichroism ( CD) approach was used to examine the conformational properties of the peptides in the presence of membrane-mimetic systems ( negatively charged sodium dodecyl sulfate, SDS, and zwitterionic N-hexadecyl-N, N-dimethyl-3-ammonio-1-propanesulfonate, HPS). While the peptides bind to both monomeric and micellar SDS, no interaction occurs with HPS, evincing the contribution of electrostatic interactions. TOAC(3)-BK's EPR spectral lineshapes are broader than those of TOAC(0)-BK, indicating a more restricted degree of motion at position 3. Moreover, the motional freedom of both peptides decreased upon binding to SDS. BK and TOAC(0)-BK solution CD spectra indicate highly flexible conformations ( possibly an equilibrium between rapidly interconverting forms), while TOAC(3)-BK's spectra correspond to a more ordered structure. SDS binding induces drastic changes in BK and TOAC(0)-BK spectra, indicating stabilization of similar folds. the micelle interface promotes a higher degree of secondary structure by favoring intramolecular hydrogen bonds. in contrast, TOAC(3)-BK spectra remain essentially unchanged. These results are interpreted as due to TOAC's ring imposing a more constrained conformation. This rigidity is very likely responsible for the inability of TOAC(3)-BK to acquire the correct receptor-bound conformation, leading to loss of biological activity. On the other hand, the greater flexibility of TOAC(0)-BK and the similarity between its conformational behavior and that of the native hormone are probably related to their similar biological activity.
Assunto bradykinin
peptide conformation
spin label
structure-activity relationship
Idioma Inglês
Data 2002-01-01
Publicado em Letters in Peptide Science. Dordrecht: Kluwer Academic Publ, v. 9, n. 2-3, p. 83-89, 2002.
ISSN 0929-5666 (Sherpa/Romeo, fator de impacto)
Editor Kluwer Academic Publ
Extensão 83-89
Direito de acesso Acesso restrito
Tipo Artigo
Web of Science WOS:000183440200005

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