Importancia de residuos hidrofobicos da alca extracelular III do receptor AT1 da angiotensina II na interacao com seu ligante

Importancia de residuos hidrofobicos da alca extracelular III do receptor AT1 da angiotensina II na interacao com seu ligante

Título alternativo Importance of the hydrophobic residues of loop extracellular III of the AT1 receptor of angiotensin II in the interaction with its ligands
Autor Zalcberg, Heloisa Autor UNIFESP Google Scholar
Resumo The role of the external third loop (EC-3) of the angiotensin II (AII) AT1, receptor for the interaction with its ligand was investigated by performing triple simuitaneous mutation of L262, L265 and L268 for Asp ([L3D3]AT1), in addition to two single mutantions of Leu265 [L265A]AT1, and L268, [L268R]AT1. The mutants were permanently transfected to Chinese hamster ovary cells (CHO). Binding assays showed that [L3D3]AT1, had very low affinity to Ali and DuP753 whereas its binding to [Sar1,Leu8-AII was not detectable. However no great changes were observed towards [L265A]AT1 and to [L268R]AT1 which produced lC5O values similar to that obtained with wild type receptor.(control) The inositol phosphate responses to AII was much drastically reduced in [L3D3]AT1. Therefore the ED50 value and the maximal effect were significantiy lower that those of wild type. It was also observed that the expression of [L3D3]AT1 was drasticaily reduced. However [L268R]AT1 and [L265A]AT1 were able to stimulate inositol phosphate formation and its maximal effect not significantly different from the controls. These effects could be only detected when multiple but not single mutations were performed. Moreover the hydrophobic residues located in this N-terminal region of EC-3 should be substituted for residues bearing charges. From these results and from the literature it is suggested that AII was less affected than [Sar1,Leu8]-AII due to its strong interactions with transmembrane residues of the receptor while the extracellular residues seem to be more important to the interactions of [Sar1,Leu8]-AII with the receptor. This could explain why [Sar1,Leu8]-AII was more affected by the mutations of [L3D3]AT1 than AII. On the other hand as DuP753 partially share some residues such as Lysl99 and His256 for interaction with AII this could explain the similar effect exerted by [L3D3]AT1 on both ligands. These resuits suggest that the hydrophobic residues located in the EC-3, close to heiix VI are critical to maintain the stability of ligand binding
Assunto Angiotensina II
Transdução de Sinal
Idioma Português
Data 1999
Publicado em São Paulo: [s.n.], 1999. 81 p. ilus.
Editor Universidade Federal de São Paulo (UNIFESP)
Extensão 81 p.
Direito de acesso Acesso restrito
Tipo Tese de doutorado

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