Conformational effects of amino acid substitutions in the P-glycoprotein of the mdr 1 gene.
The P-glycoprotein of the mdr 1 gene is responsible for the phenomenon of multidrug resistance in human cells. The presumed drug-binding site of the wild-type P-glycoprotein contains a glycine at position 185. A mutant P-glycoprotein which contains valine at this position causes cells to retain resistance to colchicine, but to lose cross-resistance to other drugs such as the chemotherapeutic agents vinblastine and Adriamycin. This has been hypothesized to be due to a conformational change in the protein induced by the amino acid substitution. Using conformational energy analysis, we have determined the allowed three-dimensional structures for the wild-type and mutant proteins in the region of position 185. The results indicate that the wild-type protein adopts a unique left-handed conformation at position 185 which is energically unfavorable for the protein with L-amino acids (including valine) at this position. This conformational change induced by amino acid substitutions for Gly 185 could explain the differences in binding to the P-glycoprotein of various drugs and, hence, the differences in drug resistance exhibited by various cell lines expressing these proteins.
Brandt-Rauf
P W
PW
Department of Medicine, Columbia-Presbyterian Medical Center, New York 10032.
Lee
G
G
Carty
R P
RP
Pincus
M R
MR
Chen
J M
JM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004351:Drug Resistance / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics; D010446:Peptide Fragments / Q000032:analysis*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D010446:Peptide Fragments