Hans MoldenhauerIgnacio Díaz-FranulicHoracio PobleteNaranjo, DavidDavidNaranjo2025-04-122025-04-122019-07-0110.7554/elife.461702-s2.0-85070658086https://cris-uv-2.scimago.es/handle/123456789/1797WOS:000477678300001In silico and in vitro studies have made progress in understanding protein-protein complex formation; however, the molecular mechanisms for their dissociation are unclear. Protein-protein complexes, lasting from microseconds to years, often involve induced-fit, challenging computational or kinetic analysis. Charybdotoxin (CTX), a peptide from the Leiurus scorpion venom, blocks voltage-gated K+-channels in a unique example of binding/unbinding simplicity. CTX plugs the external mouth of K+-channels pore, stopping K+-ion conduction, without inducing conformational changes. Conflicting with a tight binding, we show that external permeant ions enhance CTX-dissociation, implying a path connecting the pore, in the toxin-bound channel, with the external solution. This sensitivity is explained if CTX wobbles between several bound conformations, producing transient events that restore the electrical and ionic trans-pore gradients. Wobbling may originate from a network of contacts in the interaction interface that are in dynamic stochastic equilibria. These partially-bound intermediates could lead to distinct, and potentially manipulable, dissociation pathways.enacceso abiertoBiologyBiochemistry, Genetics And Molecular BiologyImmunology And MicrobiologyMedicineNeurosciencearticle