K363T
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialLysine → Threonine at position 363 in a connecting loop. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.874, DynaMut2 ΔΔG -0.43 kcal/mol (destabilising). Charge-loss variant adjacent to T361 (T361I Atlas card).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | I359 | I359 | Preserved |
| Hydrogen bond | C360 | C360 | Preserved |
| Hydrogen bond | Q366 | Q366 | Preserved |
| Hydrogen bond | D367 | D367 | Preserved |
| Hydrogen bond | — | P404 | Gained |
| Hydrogen bond | S630 | — | Lost |
| Polar contact | I359 | I359 | Preserved |
| Polar contact | C360 | C360 | Preserved |
| Polar contact | T361 | T361 | Preserved |
| Polar contact | F365 | F365 | Preserved |
| Polar contact | Q366 | Q366 | Preserved |
| Polar contact | D367 | D367 | Preserved |
| Polar contact | S630 | — | Lost |
| Van der Waals | — | I359 | Gained |
| Van der Waals | — | T361 | Gained |
| Van der Waals | F365 | F365 | Preserved |
| Van der Waals | D367 | — | Lost |
| Van der Waals | S630 | — | Lost |
| Hydrophobic | P404 | — | 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 at very low frequency in gnomAD.
Structural Context
Position 363 sits in a connecting loop, two residues from T361 (T361I Atlas card). The AlphaFold model places K363 within 5 Å of LEU362 (2.5 Å), VAL364 (2.5 Å), CYS360 (3.6 Å), ILE359 (3.8 Å), and GLN366 (4.2 Å).
The wild-type lysine at 363 is the partner residue identified in the T361I Atlas card — T361's hydroxyl was hypothesized to H-bond with K363's amine. K363T replaces lysine with threonine, which is precisely the residue that T361I introduced at the wild-type T position. The K363 amine is replaced by a hydroxyl.
This means K363T and T361I together replace the wild-type T361-K363 H-bond pair (hydroxyl-amine) with a T361-T363 pair (hydroxyl-hydroxyl in the T361 variant; or the wild-type T plus T363 in the K363T variant). The geometry changes but H-bonding may persist.
The |ΔΔG| of 0.43 reflects modest fold cost. AlphaMissense's 0.874 + Wolfram 1 confirm severe functional consequence — the partner-recognition geometry depends on the precise wild-type chemistry, not just the H-bonding capacity.
Druggability Assessment
Mechanism is disruption of the T361-K363 H-bond pair. Therapeutic strategy: same microregion as T361I.
Why this matters
Feed this card to Wolfram Intelligence
Download the K363T 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.