D367Y
Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorialAspartate → Tyrosine at position 367 in a connecting loop. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.685, ΔΔG +0.53 STABILISING.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | H401 | — | Lost |
| Hydrogen bond | K363 | K363 | Preserved |
| Hydrogen bond | V364 | — | Lost |
| Hydrogen bond | A370 | A370 | Preserved |
| Hydrogen bond | W371 | W371 | Preserved |
| Hydrogen bond | P404 | — | Lost |
| Polar contact | K363 | K363 | Preserved |
| Polar contact | V364 | V364 | Preserved |
| Polar contact | A370 | A370 | Preserved |
| Polar contact | W371 | W371 | Preserved |
| Polar contact | — | H401 | Gained |
| Aromatic / π | — | F264 | Gained |
| Aromatic / π | — | H401 | Gained |
| Carbonyl | A370 | A370 | Preserved |
| Van der Waals | K363 | — | Lost |
| Van der Waals | — | K369 | Gained |
| Van der Waals | — | H401 | Gained |
| Hydrophobic | — | I259 | Gained |
| Hydrophobic | — | F264 | Gained |
| Hydrophobic | — | K363 | Gained |
| Hydrophobic | — | A370 | Gained |
| Hydrophobic | — | H401 | Gained |
| Hydrophobic | — | P404 | Gained |
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 at very low frequency in gnomAD.
Structural Context
Position 367 in connecting loop. Neighbors: GLN366 (2.5 Å), SER368 (2.5 Å), VAL364 (3.7 Å — near K363T), LYS363 (3.8 Å — partner of K363T!). The K363 contact is structurally significant: D367 wild-type likely salt-bridges with K363.
Replacing D367 with tyrosine eliminates the salt-bridge potential. The variant fold stabilises (+0.53) because the aromatic ring packs into the local environment. AM 0.685 + Wolfram 1 confirm severe consequence. Mechanism is loss of D367-K363 salt bridge.
Druggability Assessment
Mechanism: loss of D367-K363 salt bridge. Therapeutic: same K363 microregion as K363T.
Why this matters
Feed this card to Wolfram Intelligence
Download the D367Y 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.