ISSN:
1440-1681
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
〈list xml:id="l1" style="custom"〉1Several residues critically involved in AT1 receptor ligand-binding and activation have now been identified based on mutational and biochemical studies.2Asp281 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.3Agonist 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.4The 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.5Asp1 of AngII forms an ion-pair with His183, which stabilizes the receptor-bound conformation of AngII but is not critical for receptor activation.6These interactions and the involvement of other residues in stabilizing the wild-type receptor conformation or in receptor/G-protein coupling are considered here.7Despite 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1111/j.1440-1681.1996.tb02815.x
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