Atomic determinants of BK channel activation by polyunsaturated fatty acids

作者：Tian Yutao^*; Aursnes Marius; Hansen Trond Vidar; Tungen Jorn Eivind; Galpin Jason D; Leisle Lilia; Ahern Christopher A; Xu Rong; Heinemann Stefan H; Hoshi Toshinori^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(48): 13905-13910.

DOI：10.1073/pnas.1615562113

• docosahexaenoic acid
• fish oil
• unnatural amino acids
• chemical biology
• ion-dipole

Docosahexaenoic acid (DHA), a polyunsaturated omega-3 fatty acid enriched in oily fish, contributes to better health by affecting multiple targets. Large-conductance Ca2+-and voltage-gated Slo1 BK channels are directly activated by nanomolar levels of DHA. We investigated DHA-channel interaction by manipulating both the fatty acid structure and the channel composition through the site-directed incorporation of unnatural amino acids. Electrophysiological measurements show that the para-group of a Tyr residue near the ion conduction pathway has a critical role. To robustly activate the channel, ionization must occur readily by a fatty acid for a good efficacy, and a long nonpolar acyl tail with a Z double bond present at the halfway position for a high affinity. The results suggest that DHA and the channel form an ion-dipole bond to promote opening and demonstrate the channel druggability. DHA, a marine-derived nutraceutical, represents a promising lead compound for rational drug design and discovery.

• 出版日期2016-11-29