Angiotensin II is bound to both receptors AT1 and AT2, parallel to the transmembrane domains and in an extended form

We have applied photoaffinity labelling methods combined with site-directed mutagenesis towards the two principal angiotensin II (AngII) receptors AT(1) and AT(2) in order to determine contact points between AngII and the two receptors. We have first identified the receptor contact points between an N- and a C-terminal residue of the AngII molecule and the AT(1) receptor and constructed with this stereochemical restriction a molecular model of AT(1). A similar approach with a modified procedure of photoaffinity labelling has allowed us now to determine contact points also in the AT(2) receptor. Molecular modelling of AT(2) on the rhodopsin scaffold and energy minimisation of AngII binding into this AT(2) model produced a model strikingly similar to the AT(1) structure. Superposition of the experimentally obtained contact points of AngII with AT(2) upon this model revealed excellent congruence between the experimental and modelling results. Conclusions: (i) athough AT(1) and AT(2) have quite low sequence homology, they both bind AngII with similar affinity and in an almost identical fashion, as if the ligand dictates the way it has to be bound, and (ii) in its bound form, AngII adopts an extended conformation in both AT(1) and AT(2), contrary to all previous predictions.