Key result
Mutations at AT1 residues Val254, His256, and Phe259 remarkably decreased the inositol phosphate response to angiotensin II without greatly changing ligand binding affinity.
Specific residues (Val254, His256, and Phe259) in the external third of helix VI of the AT1 receptor are essential for signal transduction but not for ligand binding.
May inform biased AT1 ligand design; leaves open clinical translation from animal models.
The role of the external third of helix VI of the angiotensin II (AII) AT1 receptor for the interaction with its ligand and for the subsequent signal transduction was investigated by individually replacing residues 252-256 by Ala, and residues 259 or 261 by Tyr, and permanently transfecting the resulting mutants to Chinese hamster ovary (CHO) cells. Binding experiments showed no great changes in affinity of any of the mutants for AII, [Sar1]-AII, or [Sar1, Leu8]-AII, but the affinity for the nonpeptide antagonist DuP753 was significantly decreased. The inositol phosphate response to AII was remarkably decreased in mutants V254A, H256A, and F259Y. These results indicate that AT1 residues Val254, His256, and Phe259 are not involved in ligand binding but participate in signal transduction. Based in these results and in others from the literature, it is suggested that, in addition to the His256 imidazole ring, the Phe259 aromatic ring interacts with the AII's Phe8, thus contributing to the signal-triggering mechanism.
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Han et al. (1998) studied this question. Site-directed mutagenesis of AT1 receptor residues 252-256, 259, or 261 was evaluated on Ligand binding affinity and inositol phosphate response. Mutations at AT1 residues Val254, His256, and Phe259 remarkably decreased the inositol phosphate response to angiotensin II without greatly changing ligand binding affinity.
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