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

• 1 Several residues critically involved in AT₁ receptor ligand-binding and activation have now been identified based on mutational and biochemical studies.
• 2 Asp²⁸¹ and Lys¹⁹⁹ of the rat AT₁ receptor ion-pair with Arg² and the Phe³ α-COOH of angiotensin II (AngII), respectively, and the Asp²⁸¹/Arg² interaction is critical for full agonist activity.
• 3 Agonist activity of AngII also requires an interaction of the Phe² side chain with His²⁵⁶, which is achieved by docking of the α-COOH with Lys¹⁹⁹. Non-peptide agonists interact with Lys¹⁹⁹ and His²⁵⁶ 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 Lys¹⁹⁹ and His²⁵⁶. However, this interaction does not involve a conventional salt bridge, but rather an unusual lysine-aromatic interaction.
• 5 Asp¹ of AngII forms an ion-pair with His¹⁸³, 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 AT₁ receptor coupling to multiple G-proteins and the in vivo role of receptor down-regulation.