Tandem sulfur-containing amino acids are epicritical determinants of dopamine D(2) receptor pharmacology.
The conserved aspartic acid that is required for ligand binding to the dopamine D(2) receptor is followed by three tandem sulfur-containing amino acids. While previous point mutation studies did not reveal any single one of these residues as being critical for ligand binding, we now show that simultaneously substituting all three with isovolumetric, non sulfur-containing amino acids results in large decreases in the binding affinity for dopamine, (-)-raclopride and 7-(-4(4-(2, 3-dichlorophenyl)-1-piperazinyl)butyloxy)-3, 4-dihydro-2(1H)-quinolinone (aripiprazole), but not for methylspiperone or allosteric modulators.
Schetz
J A
JA
Molecular Neuropharmacology Section, Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5C-108, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Sibley
D R
DR
D000603:Amino Acids, Sulfur / Q000378:metabolism*; D000818:Animals; D000068180:Aripiprazole; D001224:Aspartic Acid / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D004298:Dopamine / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D010879:Piperazines / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D015363:Quinolones / Q000378:metabolism; D020891:Raclopride / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
D000603:Amino Acids, Sulfur; D008024:Ligands; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D001224:Aspartic Acid; D020891:Raclopride; D000068180:Aripiprazole; D004298:Dopamine