Computer simulations were performed on models of the β2-adrenergic receptor dimer, including the 5-6 domain swapped dimer. The calculated energies of all the dimers on the domain swapping pathway are similar, suggesting that domain swapping is energetically feasible. Novel experimental support for domain swapping was obtained from the correlated mutations amongst the external residues of the known β2-adrenergic receptors. These occur mainly at the 5-6 interface at precisely the locations predicted by the simulations. Many aspects of G-protein coupled receptor activation which hitherto had no clear molecular explanation are discussed in terms of this novel domain swapping mechanism.
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