Structural analysis of the binding of <i>myo</i> ‐inositol pentakisphosphates by the C‐terminal PH domain of pleckstrin
Bibliographic record
Abstract
Pleckstrin, the major substrate of protein kinase C in platelets, contains prototypic N‐ and C‐terminal pleckstrin homology (PH) domains believed to mediate the binding of the protein to signaling phospholipids. The C‐terminal PH domain of pleckstrin (C‐PH) binds particularly well to phosphatidylinositol 3,4‐bisphosphate [PtdIns(3,4) P 2 ]. The relative abilities of different myo ‐inositol phosphates to inhibit the binding of C‐PH to large unilamellar vesicles containing 5 mol% PtdIns(3,4) P 2 were evaluated. Unexpectedly, Ins(1,3,4) P 3 was a poor inhibitor (IC 50 , ~60 μM), whereas the two pentakisphosphates, Ins(1,2,3,5,6) P 5 and Ins(1,2,3,4,5) P 5 were strong inhibitors (IC 50 values 2.2 μM and <1.0 μM, respectively). X‐ray crystal structures of C‐PH in the unbound (2.1 Å), Ins(1,2,3,5,6) P 5 ‐bound (1.35 Å) and Ins(1,2,3,4,5) P 5 ‐bound (1.65 Å) forms were obtained. This structural analysis showed that the binding pocket undergoes a facilitatory conformational change upon ligand binding. In addition, two different patterns of interaction between specific inositol phosphate residues and specific amino acids in the C‐PH binding pocket were observed, demonstrating that C‐PH is able to bind different inositol phosphates in distinct ways. This work was funded by grants to RH and MJ from the Canadian Institutes of Health Research. SGJ is a recipient of a Canadian Institutes of Health Research Master's Award.
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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 | 0.000 |
| 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".