Aliphatic amino acids in helix VI of the AT(1) receptor play a relevant role in agonist binding and activity

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dc.contributor.authorCorrêa, Silvana Aparecida Alves [UNIFESP]
dc.contributor.authorZalcberg, H.
dc.contributor.authorHan, S. W.
dc.contributor.authorOliveira, L.
dc.contributor.authorCosta-Neto, C. M.
dc.contributor.authorPaiva, ACM
dc.contributor.authorShimuta, S. I.
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.date.accessioned2016-01-24T12:33:25Z
dc.date.available2016-01-24T12:33:25Z
dc.date.issued2002-06-15
dc.description.abstractAngiotensin II (AII) AT(1) receptor mutants with replacements of aliphatic amino acids in the distal region of helix VI and the adjoining region of the third extracellular loop (EC-3) were expressed in Chinese hamster ovary (CHO) cells to determine their role in ligand binding and activation. the triple mutant [L262D, L265D, L268D]AT(1) (L3D) showed a marked reduction in affinity for All and for non-peptide (losartan) and peptide ([Sar(1)Leu(8)]All) antagonists; in functional assays using inositol phosphate (IP) accumulation, the relative potency and the maximum effect of All were reduced in L3D. Replacement of Leu(268) (in EC-3) and Leu(262) (in the transmembrane domain) by aspartyl residues did not cause significant changes in the receptor's affinity for the ligands and in IP production. in contrast, the point mutation L265D, at helix VI, markedly decreased affinity and ability to stimulate phosphatidylinositol turnover. Molecular modeling of the AT(1) receptor based on a recent crystal structure of rhodopsin, suggests that the side chain of Leu(265) but not that of Leu(262) is facing a cleft between helices V and VI and interacts with the lipid bilayer, thus helping to stabilize the receptor structure near the Lys(199) residue of helix V in the agonist binding site which is necessary for full activity. (C) 2002 Elsevier Science B.V. All rights reserved.en
dc.description.affiliationUniversidade Federal de São Paulo, Escola Paulista Med, Dept Biophys, BR-04023060 São Paulo, Brazil
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Escola Paulista Med, Dept Biophys, BR-04023060 São Paulo, Brazil
dc.description.sourceWeb of Science
dc.format.extent33-38
dc.identifierhttp://dx.doi.org/10.1016/S0167-0115(02)00033-2
dc.identifier.citationRegulatory Peptides. Amsterdam: Elsevier B.V., v. 106, n. 1-3, p. 33-38, 2002.
dc.identifier.doi10.1016/S0167-0115(02)00033-2
dc.identifier.issn0167-0115
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/26897
dc.identifier.wosWOS:000177027100006
dc.language.isoeng
dc.publisherElsevier B.V.
dc.relation.ispartofRegulatory Peptides
dc.rightsinfo:eu-repo/semantics/restrictedAccess
dc.rights.licensehttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dc.subjectangiotensin IIen
dc.subjectmutant receptorsen
dc.subjectCHO cellsen
dc.subjectreceptor bindingen
dc.subjectinositol phosphateen
dc.titleAliphatic amino acids in helix VI of the AT(1) receptor play a relevant role in agonist binding and activityen
dc.typeinfo:eu-repo/semantics/article
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