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Vol. 56, Issue 6, 1116-1126, December 1999
Center for Molecular Recognition (M.M.S., J.A.B., V.C.,
M.S., J.A.J.) and Departments of Psychiatry and Pharmacology (J.A.J.),
Columbia University College of Physicians and Surgeons, New York, New
York; Department of Physiology and Biophysics, Mount Sinai School of
Medicine, New York, New York (J.A.B.); F. Hoffmann-La Roche Ltd.,
Pharma Preclinical Research, Basel, Switzerland (D.S.H., T.G.); and
Howard Hughes Medical Institute (T.P.S.) and Laboratory of Molecular
Biology and Biochemistry (L.S., T.P.S.), Rockefeller University, New
York, New York
Conserved features of the sequences of dopamine receptors and of
homologous G-protein-coupled receptors point to regions, and amino acid
residues within these regions, that contribute to their ligand binding
sites. Differences in binding specificities among the
catecholamine receptors, however, must stem from their nonconserved
residues. Using the substituted-cysteine accessibility method, we have
identified the residues that form the surface of the water-accessible
binding-site crevice in the dopamine D2 receptor. Of approximately 80 membrane-spanning residues that differ between the D2 and D4 receptors,
only 20 were found to be accessible, and 6 of these 20 are conservative
aliphatic substitutions. In a D2 receptor background, we mutated the 14 accessible, nonconserved residues, individually or in combinations, to
the aligned residues in the D4 receptor. We also made the reciprocal
mutations in a D4 receptor background. The combined substitution of
four to six of these residues was sufficient to switch the affinity of
the receptors for several chemically distinct D4-selective antagonists by three orders of magnitude in both directions (D2- to D4-like and D4-
to D2-like). The mutated residues are in the second, third, and seventh
membrane-spanning segments (M2, M3, M7) and form a cluster in the
binding-site crevice. Mutation of a single residue in this cluster in
M2 was sufficient to increase the affinity for clozapine to D4-like
levels. We can rationalize the data in terms of a set of chemical
moieties in the ligands interacting with a divergent aromatic
microdomain in M2-M3-M7 of the D2 and D4 receptors.
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