Discovering Targetable Conformation of RhoA Mutant by Integrating Native Mass Spectrometry, Ultraviolet Photodissociation, and X-ray Diffraction - PubMed
4 hours ago
- #RhoA mutant
- #drug discovery
- #conformational dynamics
- Pathogenic mutations in Ras superfamily proteins present challenges for drug development due to subtle, dynamic conformational changes.
- Integration of X-ray crystallography, native mass spectrometry (nMS), and ultraviolet photodissociation (UVPD) revealed a cryptic conformation in the RhoA Y42C mutant.
- nMS-UVPD identified the dominant conformation, an enhanced Mg2+-locked state, overcoming ambiguities from crystallography alone.
- The mutation impairs GTP hydrolysis, revealing a hidden druggable pocket near Cys42.
- A covalent inhibitor was identified, targeting the newly exposed pocket.
- This integrated approach provides a strategy for targeting dynamic, 'undruggable' protein mutants.