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Intermediate-conductance (K Ca 3.1) and small-conductance (K Ca 2) calcium-activated K + channels are gated by calcium binding to calmodulin (CaM) molecules associated with the calmodulin-binding domain (CaM-BD) of these channels. The existing K Ca activators, such as naphtho[1,2- d ]thiazol-2-ylamine (SKA-31), 6,7-dichloro-1 H -indole-2,3-dione 3-oxime (NS309), and 1-ethylbenzimidazolin-2-one (EBIO), activate both channel types with similar potencies. In a previous chemistry effort, we optimized the benzothiazole pharmacophore of SKA-31 toward K Ca 3.1 selectivity and identified 5-methylnaphtho[2,1- d ]oxazol-2-amine (SKA-121), which exhibits 40-fold selectivity for K Ca 3.1 over K Ca 2.3. To understand why introduction of a single CH 3 group in five-position of the benzothiazole/oxazole system could achieve such a gain in selectivity for K Ca 3.1 over K Ca 2.3, we first localized the binding site of the benzothiazoles/oxazoles to the CaM-BD/CaM interface and then used computational modeling software to generate models of the K Ca 3.1 and K Ca 2.3 CaM-BD/CaM complexes with SKA-121. Based on a combination of mutagenesis and structural modeling, we suggest that all benzothiazole/oxazole-type K Ca activators bind relatively "deep" in the CaM-BD/CaM interface and hydrogen bond with E54 on CaM. In K Ca 3.1, SKA-121 forms an additional hydrogen bond network with R362. In contrast, NS309 sits more "forward" and directly hydrogen bonds with R362 in K Ca 3.1. Mutating R362 to serine, the corresponding residue in K Ca 2.3 reduces the potency of SKA-121 by 7-fold, suggesting that R362 is responsible for the generally greater potency of K Ca activators on K Ca 3.1. The increase in SKA-121's K Ca 3.1 selectivity compared with its parent, SKA-31, seems to be due to better overall shape complementarity and hydrophobic interactions with S372 and M368 on K Ca 3.1 and M72 on CaM at the K Ca 3.1-CaM-BD/CaM interface.

Structural Determinants for the Selectivity of the Positive KCa3.1 Gating Modulator 5-Methylnaphtho[2,1-d]oxazol-2-amine (SKA-121)