THE ACTIVATION PROCESS OF THE ALPHA(1B)-ADRENERGIC RECEPTOR - POTENTIAL ROLE OF PROTONATION AND HYDROPHOBICITY OF A HIGHLY CONSERVED ASPARTATE

In this study, a quantitative approach mas used to investigate the rol e of D142, which belongs to the highly conserved E/DRY sequence, in th e activation process of the alpha(1B)-adrenergic receptor (alpha(1B)-A R). Experimental and computer-simulated mutagenesis mere performed by substituting all possible natural amino acids at the D142 site. The re sulting congeneric set of proteins together with the finding that all the receptor mutants show various levels of constitutive (agonist-inde pendent) activity enabled us to quantitatively analyze the relationshi ps between structural/dynamic features and the extent of constitutive activity. Our results suggest that the hydrophobic/hydrophilic charact er of D142, which could be regulated by protonation/deprotonation of t his residue, is an important modulator of the transition between the i nactive (R) and active (R) state of the alpha(1B)-AR. Our study repre sents an example of quantitative structure-activity relationship analy sis of the activation process of a G protein-coupled receptor.