A single amino acid substitution strongly modulates the activity and substrate specificity of the mouse mdr1 and mdr3 drug efflux pumps

P. Gros, R. Dhir, J. Croop, F. Talbot

Research output: Contribution to journalArticle

188 Scopus citations

Abstract

Specific protein domains and amino acids responsible for the apparent capacity of P-glycoprotein (mdr) to recognize and transport a large group of structurally unrelated drugs have not been identified. We have introduced a single Ser → Phe substitution within the predicted TM11 domain of mdr1 (position 941) and mdr3 (position 939) and analyzed the effect of these substitutions on the drug-resistance profiles of these two proteins. Mutations at this residue drastically altered the overall degree of drug resistance conveyed by mdr1 and mdr3. The modulating effect of this mutation on mdr1 and mdr3 varied for the drugs tested: it was very strong for colchicine and adriamycin and moderate for vinblastine. For mdr1, the Ser941 → Phe941 substitution produced a unique mutant protein that retained the capacity to confer vinblastine resistance but lost the ability to confer adriamycin and colchicine resistance. These results strongly suggest that the predicted TM11 domain of proteins encoded by mdr and ndr-like genes plays an important role in the recognition and transport of their specific substrates.

Original languageEnglish (US)
Pages (from-to)7289-7293
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume88
Issue number16
DOIs
StatePublished - 1991
Externally publishedYes

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