期刊
NATURE CHEMICAL BIOLOGY
卷 9, 期 8, 页码 507-U88出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.1271
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资金
- Deutsche Forschungsgemeinschaft [DE1482-3/2]
- P.E. Kempkes Stiftung [01/2011]
- Wellcome Trust
- US National Institutes of Health (NIH)-NIH Heart, Lung, and Blood Institute [HL055236]
- Studienstiftung des Deutschen Volkes e.V.
- BBSRC [BB/I019855/1, BB/H000267/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/B/16011, BB/H000267/1, BEP17032, B19456, BB/I019855/1] Funding Source: researchfish
Most known small-molecule inhibitors of voltage-gated ion channels have poor subtype specificity because they interact with a highly conserved binding site in the central cavity. Using alanine-scanning mutagenesis, electrophysiological recordings and molecular modeling, we have identified a new drug-binding site in Kv1.x channels. We report that Psora-4 can discriminate between related Kv channel subtypes because, in addition to binding the central pore cavity, it binds a second, less conserved site located in side pockets formed by the backsides of S5 and S6, the S4-S5 linker, part of the voltage sensor and the pore helix. Simultaneous drug occupation of both binding sites results in an extremely stable nonconducting state that confers high affinity, cooperativity, use-dependence and selectivity to Psora-4 inhibition of Kv1.x channels. This new mechanism of inhibition represents a molecular basis for the development of a new class of allosteric and selective voltage-gated channel inhibitors.
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