Interaction of LDS-751 and Rhodamine 123 with P-Glycoprotein: Evidence for Simultaneous Binding of Both Drugs
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Bibliographic record
Abstract
The P-glycoprotein efflux pump, an ABC superfamily member, can export a wide variety of hydrophobic drugs, natural products, and peptides from cells, powered by the energy of ATP hydrolysis. Transport substrates appear to first partition into the membrane and then interact with the protein within the cytoplasmic leaflet. Two drug binding sites within P-glycoprotein have been described which interact allosterically, the H-site (binds Hoechst 33342) and the R-site (binds rhodamine 123); however, the structural and functional relationship between the various binding sites appears complex. In this work, we have used fluorescence spectroscopic approaches to characterize the interaction of the transporter with LDS-751 and rhodamine 123, both of which are believed to bind to the putative R-site based on functional transport studies. By carrying out single and sequential dual fluorescence titrations of purified P-glycoprotein with the two substrates, we observed that bound LDS-751 interacted with bound rhodamine 123. Rhodamine 123 and LDS-751 showed a reciprocal negative interaction, each reducing the binding affinity of the other by 5-fold, indicating that the two compounds were simultaneously bound to the protein to form a ternary complex. Fitting of the dependence of the apparent Kd for LDS-751 binding on rhodamine 123 concentration suggested that the two compounds interacted noncompetitively. We conclude that the two-site drug binding model for P-glycoprotein requires modification. The putative R-site appears large enough to accommodate two compounds simultaneously. The locations where LDS-751 and rhodamine 123 bind are likely adjacent to each other, possibly overlapping, and may be within a hydrophobic pocket.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it