# Structural basis of KATP channel gating

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $438,407

## Abstract

PROJECT SUMMARY
ATP-sensitive potassium (KATP) channels couple cell metabolism to membrane excitability and are critical for many
physiological functions. They are unique membrane protein complexes formed by four inwardly rectifying K+
channel (Kir6.1 or Kir6.2) subunits and four sulfonylurea receptor (SUR1 or SUR2) subunits. This grant is focused
on KATP channels consisting of Kir6.2 and SUR1, which have a key role in glucose-stimulated insulin secretion in
pancreatic β-cells. Loss-of-function mutations in these channels cause congenital hyperinsulinism and
hypoglycemia, whereas gain-of-function mutations cause neonatal diabetes and in severe cases DEND
(Developmental delay, Epilepsy, and Neonatal Diabetes) syndrome. In addition, KATP gene polymorphisms
increase risk for type 2 diabetes. Our long-term goal is to understand the structure-function relationship of
KATP channels in order to develop mechanism-based therapies for disease caused by KATP dysfunction.
Over the past three funding cycles, we have made significant progress towards this goal. Most particularly,
using single-particle cryo-electron microscopy (cryoEM) we recently obtained high-resolution structures of the
channel bound with the physiological inhibitor ATP and the anti-diabetic drug glibenclamide (glyburide). This
opened a new chapter for the field, enabling us to understand the structural basis of KATP channel assembly and
gating in health and disease, at near atomic detail and in the context of full channel structure. Our group is
uniquely positioned to help lead this effort by integrating our cryoEM capability with the extensive molecular,
biochemical, and biophysical tools and knowledge we have amassed over the course of this grant. In this renewal
application, we propose to tackle the most important yet challenging problems remaining in the field. Our
overarching hypothesis is that SUR1 assembles with and regulates the function of Kir6.2 through specific
structural interactions that are regulated by physiological and pharmacological ligands. We will use a
combination of structural, molecular dynamics simulation and functional approaches to test the hypothesis in
three interwoven but independent Specific Aims. (1) Elucidate KATP channel assembly mechanisms guided by
our cryoEM structures. (2) Identify and monitor interactions between SUR1, Kir6.2, and ligands that are critical for
channel opening and closure to understand the structural mechanisms governing channel gating. (3) Determine
open state structures of KATP channels by cryoEM to understand the conformational transition during gating. The
proposal has a strong scientific premise built on our rigorous preliminary and published studies as well as a
careful review of the literature. The proposal is innovative as it will generate new structures and test conceptually
novel mechanistic hypotheses on channel gating and assembly emanated from the recent cryoEM structures.
Successful outcome will have significant impact on a...

## Key facts

- **NIH application ID:** 10102229
- **Project number:** 5R01DK066485-14
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Show-Ling Shyng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $438,407
- **Award type:** 5
- **Project period:** 2020-02-07 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102229

## Citation

> US National Institutes of Health, RePORTER application 10102229, Structural basis of KATP channel gating (5R01DK066485-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10102229. Licensed CC0.

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