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Structure-activity correlations between the angiotensin AT1 and AT2 receptors and the kinin B1 and B2 receptors in the light of chemokine CXCR4 receptor


Recent studies have revealed a high structural homology among different receptors with many conserved residues and belonging to the same family, which allow us to predict its structures using a solved structure as a template. The type 1 and type 2 angiotensin II (AngII) receptors (AT1 and AT2 respectively) and type 1 and type 2 kinin receptors (B1 and B2 respectively) belong to the G protein coupled receptors family (GPCR) bearing seven alpha helices connected by 3 extracellular loops and 3 intracellular loops and an extracellular N-terminal and an intracellular C-terminal segments. A conformational change occurs when the activated receptor is connected to the G protein which transduces the signal to the intracellular side. To predict the AT1, AT2, B1 and B2 receptors structures the rhodopsin have been used as a template, but recently the CXCR4 structure was published. CXCR4 structure is the chemokin receptor belonging to the GPCR family. This chemokin receptor contains the structural elements absent in the rhodopsin structure such as the insertion at the third extracellular loop where a Cys residue an insertion of residues in the third extracellular loop and a disulfide bond linking this loop to the N-terminal domain. It is our interest to perform the homology modeling of the AT1, AT2, B1 and B2 receptors using the CXCR4 structure as template and then submit these models to molecular dynamics simulation test, to evaluate the inter and intra-molecular interactions. Moreover, since the interactions of AT1 receptor and the AngII were widely studied, it is our interest to perform site-directed mutagenesis in the AT2 receptor (D297A, N127G e C35S) to elucidate the binding sites of the AT2 receptor. Functional tests (AMPc and [Ca2+]i) and binding tests will be carry out using the AngII and its analogs ([Sar1]-AngII, [Sar1Lys2]-AngII, [Sar1Ala2]-AngII, [Sar1Phe4]-AngII e [Sar1Ile4]-AngII). (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MARTIN, RENAN P.; FILIPPELLI-SILVA, RAFAEL; RODRIGUES, ELIETE S.; NAKAIE, CLOVIS R.; SHIMUTA, SUMA I.. A fluorimetric binding assay for angiotensin II and kinin receptors. JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS, v. 79, p. 55-59, . (07/56480-0, 11/02208-2, 14/20965-3)

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