E737K
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialGlutamate → Lysine at position 737 in lumenal domain. ClinVar Conflicting including WFS1 spectrum. AlphaMissense 0.18 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.10 (neutral). Same E737 contacted by G736R, G736S, C765R.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | H766 | — | Lost |
| Hydrogen bond | H766 | H766 | Preserved |
| Hydrogen bond | K769 | — | Lost |
| Polar contact | C765 | — | Lost |
| Polar contact | H766 | H766 | Preserved |
| Carbonyl | C765 | — | Lost |
| Van der Waals | C765 | — | Lost |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
Clinical Evidence
Observed in the general population.
Structural Context
Position 737 — the E737 hub residue itself. Neighbors: ALA738 (2.4 Å), GLY736 (2.5 Å — G736R/G736S!), HIS766 (3.8 Å — same H766 as C765R neighbor).
E737K is the variant AT the hub position that G736R, G736S, and C765R all contact. Charge-flip disrupts the entire microregion's electrostatic geometry. Three convergent Atlas variants point at E737 from their neighbor analyses; now we have the variant at the hub itself.
AM 0.18 under-call; WFS1 spectrum confirms.
Druggability Assessment
Mechanism: charge-flip at E737 hub. Therapeutic: this is the second hub residue in the Atlas (with E431). Drug discovery targets E737 microregion.
Why this matters
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Download the E737K PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.