eLifeJClub
A GCN1-independent activator of the kinase GCN2.
eLife · · Journal Article · Open access
Zhu, Emanuelli + more
Abstract ↗AI summary
The abstract is read at the publisher; the summary is JClub's.
Three structurally distinct low-micromolar GCN2 activators were identified in an in cellulo chemical screen, including one that activates GCN2 independently of GCN1.
- Why it matters: Pathogenic EIF2AK4 variants cause PVOD, and ATP pocket-binding inhibitors can reactivate some GCN2 variants, but kinase inhibition at modestly elevated concentrations limits clinical utility.
- What they did: The authors screened for GCN2 activators in cellulo and found three compounds with low micromolar stimulatory activities; one activated GCN2 without GCN1, supported by modeling and structure-activity screens.
- The result: The GCN1-independent activator is predicted to bind the GCN2 ATP pocket without protruding into the allosteric pocket or solvent, overcoming a key requirement of other GCN2 activators.
The findingWhy it mattersWhat they didThe result
- Open access
- 1 cites