Abstract
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.
- The American Society for Pharmacology and Experimental Therapeutics
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