We have shown previously that the octapeptide angiotensin II (Ang II) activates the AT, receptor through an induced-fit mechanism (Noda, K,, Feng, Y. H., Liu, X. P., Saad, Y,, Husain, A., and Karnik, S, S. (1996) Bioc...
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We have shown previously that the octapeptide angiotensin II (Ang II) activates the AT, receptor through an induced-fit mechanism (Noda, K,, Feng, Y. H., Liu, X. P., Saad, Y,, Husain, A., and Karnik, S, S. (1996) Biochemistry 35, 16435-16442). In this activation process, interactions between Tyr(4) and Phe(8) of Ang II with Asn(111) and His(256) Of the AT(1) receptor, respectively, are essential for agonism, Here we show that aromaticity, primarily, and size, secondarily, of the Tyr(4) side chain are important in activating the receptor. Activation analysis of AT(1) receptor position 111 mutants by various Ang II position 4 analogues suggests that an amino-aromatic bonding interaction operates between the residue Asn(111) of the AT(1) receptor and Ty(r)4 of Ang II. Degree and potency of AT(1) receptor activation by Ang II can be recreated by a reciprocal exchange of aromatic and amide groups between positions 4 and 111 of Ang II and the AT(1) receptor, respectively. In several other bonding combinations, set up between Ang II position 4 analogues and receptor mutants, the gain of affinity is not accompanied by gain of function, Activation analysis of position 256 receptor mutants by Ang II position 8 analogues suggests that aromaticity of Phe(8) and His256 Side chains is crucial for receptor activation;however, a stacked rather than an amino-aromatic interaction appears to operate at this switch locus. Interaction between these residues, unlike the Tyr(4):Asn(111) interaction, plays an insignificant role in ligand docking.
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