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Differences in the arrangement of the Pdr5p multidrug transporter binding pocket of Saccharomyces cerevisiae and Kluyveromyces lactis
I. Jancíková, J. Zahumenský, Y. Gbelská, D. Gášková,
Language English Country England, Great Britain
Document type Journal Article
NLK
PubMed Central
from 2015
ProQuest Central
from 2003-03-01 to 1 year ago
Health & Medicine (ProQuest)
from 2003-03-01 to 1 year ago
Oxford Journals Open Access Collection
from 2001-04-01
PubMed
28961854
DOI
10.1093/femsyr/fox073
Knihovny.cz E-resources
- MeSH
- ATP-Binding Cassette Transporters chemistry genetics metabolism MeSH
- Azoles chemistry pharmacology MeSH
- Biological Transport MeSH
- Fluorescent Dyes MeSH
- Fluorescent Antibody Technique MeSH
- Kluyveromyces drug effects metabolism MeSH
- Binding, Competitive MeSH
- Saccharomyces cerevisiae Proteins chemistry metabolism MeSH
- Saccharomyces cerevisiae drug effects metabolism MeSH
- Substrate Specificity MeSH
- Protein Binding MeSH
- Binding Sites * MeSH
- Publication type
- Journal Article MeSH
Multidrug transporters are often responsible for failure of medical treatment, since they expel a variety of structurally and functionally unrelated drugs out of the cell. We found that the fluorescent probe diS-C3(3) is a substrate of not only Pdr5p of Saccharomyces cerevisiae (ScPdr5p) but also of its less-explored Kluyveromyces lactis homologue (KlPdr5p). This enabled us to compare the ability of azoles to competitively inhibit the Pdr5p-mediated probe efflux in the two species. In K. lactis, these azoles completely inhibit probe transport by KlPdr5p and also compete with each other for transport. This indicates that the probe and the azoles are bound by the same site(s) of the KlPdr5p binding pocket. On the other hand, the azoles' capacity to inhibit the probe transport by ScPdr5p is limited, as a result of their partial cotransport with the probe. While the azoles bind to only one or two separate binding sites, the probe is able to bind to all three of them. Moreover, the bulky ScPdr5p substrate enniatin B, which effectively inhibits both probe and azole transport by the pump, has negligible effect on KlPdr5p. Our data point to a tighter arrangement of the KlPdr5p binding pocket compared to that of ScPdr5p.
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- $a Multidrug transporters are often responsible for failure of medical treatment, since they expel a variety of structurally and functionally unrelated drugs out of the cell. We found that the fluorescent probe diS-C3(3) is a substrate of not only Pdr5p of Saccharomyces cerevisiae (ScPdr5p) but also of its less-explored Kluyveromyces lactis homologue (KlPdr5p). This enabled us to compare the ability of azoles to competitively inhibit the Pdr5p-mediated probe efflux in the two species. In K. lactis, these azoles completely inhibit probe transport by KlPdr5p and also compete with each other for transport. This indicates that the probe and the azoles are bound by the same site(s) of the KlPdr5p binding pocket. On the other hand, the azoles' capacity to inhibit the probe transport by ScPdr5p is limited, as a result of their partial cotransport with the probe. While the azoles bind to only one or two separate binding sites, the probe is able to bind to all three of them. Moreover, the bulky ScPdr5p substrate enniatin B, which effectively inhibits both probe and azole transport by the pump, has negligible effect on KlPdr5p. Our data point to a tighter arrangement of the KlPdr5p binding pocket compared to that of ScPdr5p.
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