TY - JOUR T1 - Mutagenesis and Modelling of the α<sub>1b</sub>-Adrenergic Receptor Highlight the Role of the Helix 3/Helix 6 Interface in Receptor Activation JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1025 LP - 1032 DO - 10.1124/mol.61.5.1025 VL - 61 IS - 5 AU - Peter J. Greasley AU - Francesca Fanelli AU - Olivier Rossier AU - Liliane Abuin AU - Susanna Cotecchia Y1 - 2002/05/01 UR - http://molpharm.aspetjournals.org/content/61/5/1025.abstract N2 - Computer simulations on a new model of the α1b-adrenergic receptor based on the crystal structure of rhodopsin have been combined with experimental mutagenesis to investigate the role of residues in the cytosolic half of helix 6 in receptor activation. Our results support the hypothesis that a salt bridge between the highly conserved arginine (R1433.50) of the E/DRY motif of helix 3 and a conserved glutamate (E2896.30) on helix 6 constrains the α1b-AR in the inactive state. In fact, mutations of E2896.30 that weakened the R1433.50-E2896.30 interaction constitutively activated the receptor. The functional effect of mutating other amino acids on helix 6 (F2866.27, A2926.33, L2966.37, V2996.40,V3006.41, and F3036.44) correlates with the extent of their interaction with helix 3 and in particular with R1433.50 of the E/DRY sequence. ER -