Protein Engineering, Vol 11, 1181-1193, Copyright © 1998 by Oxford University Press
PR Gouldson, CR Snell, RP Bywater, C Higgs and CA Reynolds
Computer simulations were performed on models of the beta2-adrenergic
receptor dimer, including 5,6-domain swapped dimers which have been
proposed as the active, high affinity form (here the dimer interface lies
between helices 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 propranolol. In the presence of agonist the energy of the domain swapped
dimer is significantly lowered. Analysis of the dimer structure suggests
that the agonist-induced conformational change optimizes the helix-helix
interactions at the 5-6 interface. An antagonist on the other hand has
little effect on these interactions. These observations are consistent with
the hypothesis that the agonist functions by shifting the equilibrium in
favour of the domain swapped dimer. Indirect support for the domain
swapping hypothesis was obtained from the correlated mutations amongst the
external residues of the known beta2-adrenergic receptors. These occur
mainly at the 5-6 interface at precisely the locations predicted by the
simulations; site- directed mutagenesis data in support of a functional
role for these lipid-facing correlated residues is presented. The article
includes a review of the experimental evidence for G-protein coupled
receptor dimerization. Many other aspects of G-protein coupled receptor
activation are discussed in terms of this domain swapping hypothesis
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Domain swapping in G-protein coupled receptor dimers
Department of Biological Sciences, University of Essex, Colchester, UK.
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