Fig. 6: Structural basis for antagonist selectivity on T-type Cav channels.
From: Structural basis for human Cav3.2 inhibition by selective antagonists
a Structure-guided sequence analysis to identify the determinants for antagonist selectivity. Sequence comparison of human Cav channels for the antagonist-binding residues is shown. The dashes represent residues in other subtypes that are identical to the corresponding ones in Cav3.2. b Functional validation of residues critical to TTA-A2 selectivity. Several residues in Cav3.2 were mutated to corresponding ones in the HVA channels. The responses of these mutants to TTA-A2 were examined through whole-cell patch-clamp recordings. c A magnified view of the coordination of TTA-P2 and ML218 in the superimposed structures of Cav3.2-TP and Cav3.2-ML. d F1007L confers Cav3.2 resistance to ML218, but not TTA-P2. Experimental details are provided in Materials and Methods and Supplementary information, Figs. S9–S11, and Tables S3 and S4. e Potential molecular basis for the distinct responses to TTA-P2 and ML218 by Cav3.2-F1007L. The additional fluorine atom in the piperidine ring of TTA-P2 may interfere with the essential π-H interaction between Phe1007 and the piperidine ring, potentially resulting in lower potency on Cav3.2, which is largely unaffected by the Leu substitution.
