Exploring an Intracellular Allosteric Site of CC-Chemokine Receptor 4 from 3D Models, Probe Simulations, and Mutagenesis
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Bibliographic record
Abstract
High Resolution Image Download MS PowerPoint Slide We applied our previously developed probe confined dynamic mapping protocol, which combines enhanced sampling molecular dynamics (MD) simulations and fragment-based approaches, to identify the binding site of GSK2239633A ( N -[[3-[[3-[(5-chlorothiophen-2-yl)sulfonylamino]-4-methoxyindazol-1-yl]methyl]phenyl]methyl]-2-hydroxy-2-methylpropanamide), a selective CC-chemokine receptor type 4 (CCR4) negative allosteric modulator, using CCR4 homology and AlphaFold models. By comparing the performance across five computational models, we identified conserved (K310 8.49 and Y304 7.53 ) and non-conserved (M243 6.36 ) residue hotspots for GSK2239633A binding, which were validated by mutagenesis and bioluminescence resonance energy transfer assay. Further analysis of 3D models and MD simulations highlighted the pair of residues 6.36 and 7.56 that might account for antagonist selectivity among chemokine receptors. Our in silico protocol provides a promising approach for characterizing ligand binding sites in membrane proteins, considering receptor dynamics and adaptability and guiding protein template selection for ligand design.
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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