Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 31, Pages 10774-10778Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0802850105
Keywords
block; inhibition; K channel; tertiapin; toxin
Categories
Funding
- NIGMS NIH HHS [GM61929, R01 GM061929] Funding Source: Medline
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Inward-rectifier K+ (Kir) channels play many important biological roles and are emerging as important therapeutic targets. Subtype-specific inhibitors would be useful tools for studying the channels' physiological functions. Unfortunately, available K+ channel inhibitors generally lack the necessary specificity for their reliable use as pharmacological tools to dissect the various kinds of K+ channel currents in situ. The highly conserved nature of the inhibitor targets accounts for the great difficulty in finding inhibitors specific for a given class of K+ channels or, worse, individual subtypes within a class. Here, by modifying a toxin from the honey bee venom, we have successfully engineered an inhibitor that blocks Kir1 with high (1 nM) affinity and high (> 250-fold) selectivity over many commonly studied Kir subtypes. This success not only yields a highly desirable tool but, perhaps more importantly, demonstrates the practical feasibility of engineering subtype-specific K+ channel inhibitors.
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