Opposite effects of 1,4-dihydropyridine (DHP) agonists and antagonists on the L-type calcium channels are a challenging problem. Cryo-EM structures visualized DHPs between the pore-lining helices S6III and S6IV in agreement with published mutational data. However, the channel conformations in the presence of DHP agonists and antagonists are virtually the same, and the mechanisms of the ligands’ action remain unclear. We docked the DHP agonist S-Bay k 8644 and antagonist R-Bay k 8644 in Cav1.1 channel models with or without π-bulges in helices S6III and S6IV. Cryo-EM structures of the DHP-bound Cav1.1 channel show a π-bulge in helix S6III but not in S6IV. The antagonist’s hydrophobic group fits into the hydrophobic pocket formed by residues in S6IV. The agonists’ polar NO2 group is too small to fill up the pocket. A water molecule could sterically fit into the void space, but its contacts with isoleucine in helix S6IV (motif INLF) would be unfavorable. In a model with π-bulged S6IV, this isoleucine turns away from the DHP molecule and its position is occupied by the asparagine from the same motif INLF. The asparagine provides favorable contacts for the water molecule at the agonist’s NO2 group but unfavorable contacts for the antagonist’s methoxy group. In our models, the DHP antagonist stabilizes entirely α-helical S6IV. In contrast, the DHP agonist stabilizes π-bulged helix S6IV whose C-terminal part turned and rearranged the activation-gate region. This would stabilize the open channel. Thus, agonists, but not antagonists, would promote channel opening by stabilizing π-bulged helix S6IV.

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