The active state of the AT₁ angiotensin receptor is generated by angiotensin II induction

In the current model of receptor activation, the given hormone is not involved in the conversion of the inactive receptor (R) to the fully active state (R*). Rather, it preferentially selects the activated receptor conformation, thereby shifting the equilibrium toward R*. The hormone angiotensin II (Ang II) contains two residues, Tyr⁴ and Phe⁸, that are essential for agonism. We show that the conserved Asn¹¹¹ in transmembrane helix III of the AT₁ angiotensin receptor directly interacts with the Tyr⁴ side chain. A decrease in the size of the Asn¹¹¹ side chain induces an intermediate activated receptor conformation (R'). The Ang II analogue [Sar¹,Ile⁴,Ile⁸]Ang II fully activates the N111G mutant, indicating that either the transition from R' to R* or the stabilization of the R* state requires binding by Ang II but not its Tyr⁴ and Phe⁸ side chains. In contrast, [Sar¹,Ile⁴,Ile⁸]Ang II binds to but does not activate the wild- type AT₁ receptor (R), suggesting that in the wild-type receptor spontaneous occurrence of R' and R* states is rare. Thus, Ang II through interactions involving Tyr⁴ and Phe⁸ induces a transition from R to R' and through unspecified interactions induces transition from R' to R* states rather than stabilizing the spontaneously generated R* state by 'conformational selection'.