Analysis of the Divalent Cation Blocking in Ion Channels by Crystal Structure and Molecular Dynamics Simulations

In this study, we elucidated the molecular mechanism of the divalent cation block by reproducing the divalent cation block in NavAb. The X-ray crystal structure of divalent-cation-block mutants show electron density in the ion transmission pathway of the divalent cation blocked mutants, indicating that the mutations increasing the hydrophilicity of the inner vestibule of the pore domain enable a divalent cation to stack into the ion pathway. In molecular dynamics simulations, the stacked calcium ion repels the sodium ions near the channel lumen's entrance at the selective filter's bottom. These results suggest the primary process of the divalent cation block mechanism in tetrameric cation channels and suggest a process of functional acquisition in ion channel evolution.PMID:38692927 | DOI:10.1248/yakushi.23-00178-3
Source: Yakugaku Zasshi : Journal of the Pharmaceutical Society of Japan - Category: Drugs & Pharmacology Authors: Source Type: research