Crystal structures of human 17β‐hydroxysteroid dehydrogenase type 1 complexed with estrone and <scp>NADP</scp><sup>+</sup> reveal the mechanism of substrate inhibition
Bibliographic record
Abstract
Human 17β‐hydroxysteroid dehydrogenase type 1 (17β‐ HSD 1) catalyses the last step in estrogen activation and is thus involved in estrogen‐dependent diseases ( EDD s). Unlike other 17β‐ HSD members, 17β‐ HSD 1 undergoes a significant substrate‐induced inhibition that we have previously reported. Here we solved the binary and ternary crystal structures of 17β‐ HSD 1 in complex with estrone (E1) and cofactor analog NADP + , demonstrating critical enzyme‐substrate‐cofactor interactions. These complexes revealed a reversely bound E1 in 17β‐ HSD 1 that provides the basis of the substrate inhibition, never demonstrated in estradiol complexes. Structural analysis showed that His 221 is the key residue responsible for the reorganization and stabilization of the reversely bound E1, leading to the formation of a dead‐end complex, which exists widely in NADP (H)‐preferred enzymes for the regulation of their enzymatic activity. Further, a new inhibitor is proposed that may inhibit 17β‐ HSD 1 through the formation of a dead‐end complex. This finding indicates a simple mechanism of enzyme regulation in the physiological background and introduces a pioneer inhibitor of 17β‐ HSD 1 based on the dead‐end inhibition model for efficiently targeting EDD s. Databases Coordinates and structure factors of 17β‐ HSD 1‐E1 and 17β‐ HSD 1‐E1‐ NADP + have been deposited in the Protein Data Bank with accession code 6MNC and 6MNE respectively. Enzymes 17β‐hydroxysteroid dehydrogenase type 1 (17β‐ HSD 1) EC 1.1.1.62 .
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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 | 0.000 | 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 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".