KATP channel structures
EMSL Project ID
50540
Abstract
ATP-sensitive potassium (KATP) channels couple cell metabolism to membrane excitability and are important for regulating hormone secretion, neuronal activity, vascular tone, and adaptive response to ischemic injuries. Dysfunction of KATP channels underlies several human diseases. Our long-term goal is to understand the structure-function relationships of KATP channels in order to develop mechanistic therapies for diseases caused by KATP channel dysfunction. KATP channels are formed by co-assembly of an inwardly rectifying K+ channel Kir6 and a sulfonylurea receptor (SUR) belong to the ABC transporter protein superfamily. There are three major KATP subtypes with distinct expression patterns and gating properties: the SUR1/Kir6.2 channel found in pancreatic endocrine cells and neurons, the SUR2A/Kir6.2 channel predominantly expressed in cardiac myocytes, and the SUR2B/Kir6.1 channel expressed in vascular smooth muscles. We have been successful in obtaining cryoEM structures of the SUR1/Kir6.2 channel in a closed conformation bound to ATP and an anti-diabetic drug called glibenclamide. In this proposal we plan to determine the structure of the SUR2A/Kir6.2 and the SUR2B/Kir6.1 channel bound to glibenclamide and ATP, with the objective of understanding the structural basis underlying the documented differential sensitivities of the three channel subtypes to ATP and glibenclamide. The research is significant to both human health and basic science. It will provide a framework for understanding how the different channel subtypes may be tailored structurally to suit the metabolic profile of the cells in which they reside. The information is also expected to facilitate design of drugs with increased specificity towards each KATP subtype.
Project Details
Start Date
2018-10-30
End Date
2021-01-31
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members