Ryanodine receptors (RyR) are key intracellular ion channels that facilitate the movement of Ca 2+ from the endoplasmic and sarcoplasmic reticulum to illicit muscle contractions in a process known as excitation-contraction coupling. Calcins are short peptides isolated from the venom of several scorpion species that have the unique ability to cross the plasma membrane, where they target RyRs. Once bound, these peptides lock the channel in a long-lasting subconductance state, in which the pore remains only partially open and conducts calcium at a reduced but stable level compared to its maximum conductance. Calcins interact with RyRs with high affinity and remarkable specificity, and structural studies have localized their binding site above the pore region, where they establish numerous contacts with the S6 extension helix. Different scorpion species produce distinct calcins, each with characteristic binding affinities and varying degrees of subconductance. Among them, opicalcin1 and vejocalcin are notable, with opicalcin1 displaying the strongest binding affinity, and vejocalcin inducing the highest degree of subconductance. To determine the molecular basis of these functional differences, we employ a multifaceted approach combining cryo-electron microscopy with molecular dynamics simulations. This approach allows us to map calcin interactions within the pore region and identify structural element that give rise to their distinct effects. In combination with molecular dynamics, these structural insights pinpoint the specific interactions responsible for inducing and stabilizing the subconductance state. Together, these findings advance our understanding of the calcin-RyR interaction and allow for structure based design of calcin inspired RyR modulators.
Bader et al. (Sun,) studied this question.