Proceedings of the Symposium ‘Angiotensin AT₁ Receptors: From Molecular Physiology to Therapeutics’: MOLECULAR DETERMINANTS OF PEPTIDE AND NON‐PEPTIDE BINDING TO THE AT₁ RECEPTOR

Several residues critically involved in AT(1) receptor ligand-binding and activation have now been identified based on mutational and biochemical studies. 2. Asp(281) and Lys(199) of the rat AT(1) receptor ion-pair with Arg(2) and the Phe(3) α-COOH of angiotensin II (AngII), respectively, and the Asp(281) /Arg(2) interaction is critical for full agonist activity. 3. Agonist activity of AngII also requires an interaction of the Phe(2) side chain with His(256), which is achieved by docking of the α-COOH with Lys(199). Non-peptide agonists interact with Lys(199) and His(256) in a similar fashion. 4. The crucial acid pharmacophores of AngII and the non-peptide antagonist, Iosartan, appear to occupy the same space within the receptor pocket. Binding of the tetrazole anion moiety of losartan involves multiple contacts, such as Lys(199) and His(256). However, this interaction does not involve a conventional salt bridge, but rather an unusual lysine-aromatic interaction. 5. Asp(1) of AngII forms an ion-pair with His(183), which stabilizes the receptor-bound conformation of AngII but is not critical for receptor activation. 6. These interactions and the involvement of other residues in stabilizing the wild-type receptor conformation or in receptor/G-protein coupling are considered here. 7. Despite these insights, considerable effort is still needed to elucidate how ligand binding induces receptor activation, what determines the specificity of AT(1) receptor coupling to multiple G-proteins and the in vivo role of receptor down-regulation.