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A conserved helix 2 Asp is required for the proper function of
many G-protein-coupled receptors. To reveal the structural basis for
the role of this residue, the additive effects of mutations at this
locus and at a conserved helix 7 locus were investigated in the
5-HT
Volume 270,
Number 28,
Issue of July 14, pp. 16683-16688, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
Receptor
receptor. All mutant receptors studied retained high
affinity agonist and antagonist binding. Whereas an Asp
Asn
mutation in helix 2 eliminated coupling, interchanging the residues at
the two positions by a second mutation of Asn
Asp in helix 7
restored receptor function. These data suggest that these residues are
adjacent in space and interact. The loss of function observed with Ala
at either position is consistent with each side chain forming hydrogen
bonds. Molecular dynamics simulations were performed on
three-dimensional computational models of agonist-receptor complexes of
both the wild-type receptor and the Asp
Asn mutant receptor.
Consonant with the lack of coupling observed for the mutant construct,
introducing the mutation into the computational model produced a
conformational change in a direction opposite to that seen from
computational simulations of activation of the wild-type receptor
model. These results implicate both loci in a common hydrogen-bonding
network underlying receptor activation by agonist.
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