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J Biol Chem, Vol. 274, Issue 1, 227-235, January 1, 1999

Structure of Two Fragments of the Third Cytoplasmic Loop of the Rat Angiotensin II AT_1A Receptor
IMPLICATIONS WITH RESPECT TO RECEPTOR ACTIVATION AND G-PROTEIN SELECTION AND COUPLING

Lorella Franzoni, Giuseppe Nicastro, Thelma A. Pertinhez, Eliandre Oliveira^¶, Clóvis R. Nakaie^¶, Antonio C. M. Paiva^¶, Shirley Schreier, and Alberto Spisni

From the Institute of Biological Chemistry, University of Parma, 43100 Parma, Italy, the  Institute of Chemistry, Department of Biochemistry, University of São Paulo, Caixa Postale 26077, 05599-970, São Paulo, Brazil, and the ^¶ Department of Biophysics, Federal University of São Paulo, Caixa Postale 04044-020, São Paulo Brazil

The structural bases that render the third intracellular loop (i3) of the rat angiotensin II AT_1A receptor one of the cytoplasmic domains responsible for G-protein coupling are still unknown. The three-dimensional structures of two overlapping peptides mapping the entire i3 loop and shown to differently interact with purified G-proteins have been obtained by simulated annealing calculations, using NMR-derived constraints collected in 70% water/30% trifluoroethanol solution. While the NH₂-terminal half, Ni3, residues 213-231, adopts a stable amphipathic -helix, extending over almost the entire peptide, a more flexible conformation is found for the COOH-terminal half, Ci3, residues 227-242. For this peptide, a cis-trans isomerization around the Lys⁶Pro⁷ peptide bond generates two exchanging isomers adopting similar conformations, with an -helix spanning from Asn⁹ to Ile¹⁵ and a poorly defined NH₂ terminus. A quite distinct structural organization is found for the sequence EIQKN, common to Ni3 and Ci3. The data do suggest that the extension and orientation of the amphipathic -helix, present in the proximal part of i3, may be modulated by the distal part of the loop itself through the Pro²³³ residue. A molecular model where this possibility is considered as a mechanism for G-protein selection and coupling is presented.

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