Native MS Shows PROTAC Linker Length and Warhead Identity Shape Ternary Complexes Differently
- Ion mobility, surface-induced dissociation and variable-temperature ESI were combined to probe BRD4–PROTAC–VCB complexes built with two BET ligands (JQ1 and I-BET726) and PEG linkers of different lengths.
- Shorter linkers held complexes in more extended shapes; longer, flexible linkers allowed relaxed, native-like conformations.
- JQ1 complexes tended to eject the PROTAC under collision, while tighter-binding I-BET726 complexes retained it; the two also melted differently.
💡 Points
Linker optimization is still mostly empirical, so orthogonal readouts of how architecture shapes the complex interface are welcome. Gas-phase data are not solution cooperativity, and I'd not rank degraders by them alone, but pairing them with cellular degradation could help rationalize why two warheads behave so differently. A preprint, so treat the conclusions as provisional until peer review.