Molecular dynamics finds a RhoJ-specific N-terminal pocket, and terconazole disrupts PAK3 binding
- RhoJ is nearly identical to Cdc42 in sequence but carries a unique N-terminal extension, which simulations show forms an allosteric pocket on binding PAK3.
- Structure-based virtual screening against that pocket flagged the antifungal terconazole as a possible binder.
- In live cells, an optimized BRET2 biosensor showed terconazole reduces the RhoJ–PAK3 interaction in a dose-dependent way.
💡 Points
Using a sequence extension absent from Cdc42 to buy selectivity is exactly how I'd attack a conserved GTPase. But terconazole is a repurposed azole with modest credentials as a starting point, and a BRET drop alone can't prove pocket engagement. I'd want mutagenesis of the N-terminal residues and a biophysical binding readout before calling this validated.
Identification and targeting of a novel drug pocket in the tumour angiogenesis regulator RhoJ ↗