Abstract

Introduction

Materials & Methods

Results

Discussion & Conclusion

References

Discussion
Board

The angiotensin II (AngII) AT₁ receptor belongs to the rhodopsin-like G-protein-coupled receptor (GPCR) family characterized by a seven transmembrane domain structure consisting of an extracellular N-terminal domain, seven transmembrane helical segments (helices I - VII) linked by three intracellular and three extracellular loops, and an intracellular C-terminal tail [1]. In this family of receptors the binding of small ligands, such as monoamines, is believed to occur within the transmembrane domains, large glycoprotein hormones appear to bind to the extracellular regions, and peptide agonists bind both to extracellular and transmembrane regions [2,3].

In an extensive mutagenesis analysis employing Ala-scan and conservative segment exchanges on the AT₁ receptor, the mutants in which the binding of AngII was most affected were Y92A, K102A, V179A, D278A, D281A, and the triple mutant (H24A,Y26A,I27A) [4]. These mutations are located in the extracellular N-terminal extension and in the loops of the receptor, suggesting that the peptide ligand binds mostly to the outer regions of the receptor. Other important contact points are Lys199, which appears to interact with AngII's C-terminal carboxyl [5,6] and Asp281, which may interact with AngII's Arg2 side-chain [7]. In contrast to the other probable peptide contact points, Lys199 is located one turn into the transmembrane region.

Mutational studies on AT₁ have also indicated that the proximal segments of intracellular loop V-VI and of the cytoplasmic tail, close to the membrane, are critical for G-protein coupling [8-14].

Concerning the signal generated by agonist-receptor binding and the activation of G-protein, mutational studies showed that the region comprising AT₁ residues 252 - 259 in helix VI is involved in initiating the signal [5,15,16], and sequence alignment data yielded a model for G-protein activation involving the side-chain of Arg126, located in the distal end of TM-III [17]. This supposition has been confirmed by mutagenesis studies [18,19] and molecular dynamics [20,21], although some doubt remains regarding the condition upon which Arg126's action is manifested [22].

In this presentation we propose to incorporate the above summarized conclusions from experimental data in a molecular model of the AT₁ receptor and of its interaction with AngII.

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