TY - JOUR
T1 - Manipulating the drug/proton antiport stoichiometry of the secondary multidrug transporter MdfA
AU - Tirosh, Osnat
AU - Sigal, Nadejda
AU - Gelman, Amir
AU - Sahar, Nadav
AU - Fluman, Nir
AU - Siemion, Shira
AU - Bibi, Eitan
N1 - Israel Science Foundation [1128/06]This work was supported by Israel Science Foundation Grant 1128/06.
PY - 2012/7/31
Y1 - 2012/7/31
N2 - Multidrug transporters are integral membrane proteins that use cellular energy to actively extrude antibiotics and other toxic compounds from cells. The multidrug/proton antiporter MdfA from Escherichia coli exchanges monovalent cationic substrates for protons with a stoichiometry of 1, meaning that it translocates only one proton per antiport cycle. This may explain why transport of divalent cationic drugs by MdfA is energetically unfavorable. Remarkably, however, we show that MdfA can be easily converted into a divalent cationic drug/≥2 proton-antiporter, either by random mutagenesis or by rational design. The results suggest that exchange of divalent cationic drugs with two (or more) protons requires an additional acidic residue in the multidrug recognition pocket of MdfA. This outcome further illustrates the exceptional promiscuous capabilities of multidrug transporters.
AB - Multidrug transporters are integral membrane proteins that use cellular energy to actively extrude antibiotics and other toxic compounds from cells. The multidrug/proton antiporter MdfA from Escherichia coli exchanges monovalent cationic substrates for protons with a stoichiometry of 1, meaning that it translocates only one proton per antiport cycle. This may explain why transport of divalent cationic drugs by MdfA is energetically unfavorable. Remarkably, however, we show that MdfA can be easily converted into a divalent cationic drug/≥2 proton-antiporter, either by random mutagenesis or by rational design. The results suggest that exchange of divalent cationic drugs with two (or more) protons requires an additional acidic residue in the multidrug recognition pocket of MdfA. This outcome further illustrates the exceptional promiscuous capabilities of multidrug transporters.
UR - http://www.scopus.com/inward/record.url?scp=84864513575&partnerID=8YFLogxK
U2 - https://doi.org/10.1073/pnas.1203632109
DO - https://doi.org/10.1073/pnas.1203632109
M3 - مقالة
SN - 0027-8424
VL - 109
SP - 12473
EP - 12478
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 31
ER -