Domain swapping in G-protein coupled receptor dimers

Computer simulations were performed on models of the beta(2)-adrenergic rec eptor dimer, including 5,6-domain swapped dimers which have been proposed a s the active, high affinity form (here the dimer interface lies between hel ices 5 and 6). The calculations suggest that the domain swapped dimer is a high energy structure in both the apo dimer and in the presence of proprano lol. In the presence of agonist the energy of the domain swapped dimer is s ignificantly lowered. Analysis of the dimer structure suggests that the ago nist-induced conformational change optimizes the helix-helix interactions a t the 5-6 interface. An antagonist on the other hand has little effect on t hese interactions. These observations are consistent with the hypothesis th at the agonist functions by shifting the equilibrium in favour of the domai n swapped dimer, Indirect support for the domain swapping hypothesis was ob tained from the correlated mutations amongst the external residues of the k nown beta(2)-adrenergic receptors. These occur mainly at the 5-6 interface at precisely the locations predicted by the simulations; site-directed muta genesis data in support of a functional role for these lipid-facing correla ted residues is presented. The article includes a review of the experimenta l evidence for G-protein coupled receptor dimerization, Many other aspects of G-protein coupled receptor activation are discussed in terms of this dom ain swapping hypothesis.