Structure‐guided probing of the leukotriene C <sub>4</sub> binding site in human multidrug resistance protein 1 (MRP1; ABCC1)
Bibliographic record
Abstract
ABSTRACT The human multidrug resistance protein 1 (hMRP1) transporter is implicated in cancer multidrug resistance as well as immune responses involving its physiologic substrate, glutathione (GSH)‐conjugated leukotriene C 4 (LTC 4 ). LTC 4 binds a bipartite site on hMRP1, which a recent cryoelectron microscopy structure of LTC 4 ‐bound bovine Mrp1 depicts as composed of a positively charged pocket and a hydrophobic (H) pocket that binds the GSH moiety and surrounds the fatty acid moiety, respectively, of LTC 4 . Here, we show that single Ala and Leu substitutions of H‐pocket hMRP1‐Met 1093 have no effect on LTC 4 binding or transport. Estrone 3‐sulfate transport is also unaffected, but both hMRP1‐Met 1093 mutations eliminate estradiol glucuronide transport, demonstrating that these steroid conjugates have binding sites distinct from each other and from LTC 4 . To eliminate LTC 4 transport by hMRP1, mutation of 3 H‐pocket residues was required (W553/M1093/W1246A), indicating that H‐pocket amino acids are key to the vastly different affinities of hMRP1 for LTC 4 vs . GSH alone. Unlike organic anion transport, hMRP1‐mediated drug resistance was more diminished by Ala than Leu substitution of Met 1093 . Although our findings generally support a structure in which H‐pocket residues bind the lipid tail of LTC 4 , their critical and differential role in the transport of conjugated estrogens and anticancer drugs remains unexplained.—Conseil, G., Arama‐Chayoth, M., Tsfadia, Y., Cole, S. P. C. Structure‐guided probing of the leukotriene C 4 binding site in human multidrug resistance protein 1 (MRP1; ABCC1). FA8EB J. 33, 10692–10704 (2019). www.fasebj.org
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How this classification was reachedexpand
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 | 0.001 | 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 | 0.001 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".