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Dynamic elucidation of drug transport pathways in human P‐glycoprotein (974.5)
Author(s) -
McCormick James,
Vogel Pia,
Wise John
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.974.5
Subject(s) - p glycoprotein , transporter , atp binding cassette transporter , extracellular , intracellular , multiple drug resistance , daunorubicin , cytoplasm , efflux , membrane transport , population , drug , chemistry , transport protein , microbiology and biotechnology , drug resistance , biochemistry , biology , pharmacology , membrane , medicine , gene , genetics , chemotherapy , environmental health
Chemotherapy resistant, recurrent cancers most commonly express members of the ABCB1 class of plasma membrane transporters, specifically MDR1 P‐glycoprotein transporter (P‐gp). At high levels of expression, the P‐gp transporter lowers the intracellular concentrations of chemotherapeutics to below effective therapeutic levels. Because P‐gp can transport a broad range of substrates, such expression leads to general multidrug resistance in the population of cancerous cells. Dynamic P‐gp models which transition through putative catalytic cycles have been previously created by us using targeted molecular dynamics simulations (TMD) with four different crystallographic conformations of related proteins. In the present study, these simulations have been expanded to include transport substrates docked into different initial sites within the drug binding domain of P‐gp. Even though drug movement in these simulations was not targeted by TMD, transport of chemotherapeutics (daunorubicin and doxorubicin) and a P‐gp transport substrate (verapamil) through the membrane by human P‐gp was observed during the putative catalytic cycles. Initial results suggest that different starting positions of transport substrate in the “open to the cytoplasm” conformation resolve into a common transport pathway through the membrane as P‐gp closes to the cytoplasm and opens to the extracellular space. Grant Funding Source : NIH 1R15GM094771 ‐ 01A1, Communities Foundations of TX