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 mdr-like genes plays an important role in the recognition and transport of their specific substrates.
journal_name
Proc Natl Acad Sci U S Aauthors
Gros P,Dhir R,Croop J,Talbot Fdoi
10.1073/pnas.88.16.7289subject
Has Abstractpub_date
1991-08-15 00:00:00pages
7289-93issue
16eissn
0027-8424issn
1091-6490journal_volume
88pub_type
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