Human TWIK-related Acid-Sensitive K+ Channel 1 (TASK1): A Target Enabling Package
- Karin E. J. Rödström1
- Aytuğ K. Kiper2
- Wei Zhang1
- Susanne Rinné2
- Ashley C. W. Pike1
- Matthias Goldstein2
- Linus Conrad3
- Martina Delbeck4
- Michael Hahn4
- Heinrich Meier4
- Magdalena Platzk4
- Andrew Quigley1
- David Speedman1
- Leela Shrestha1
- Shubhashish M.M. Mukhopadhyay1
- Nicola A. Burgess-Brown1
- Stephen J. Tucker3
- Thomas Mueller4
- Niels Decher2
- Elisabeth P. Carpenter1
- 1. Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford
- 2. Institute for Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Marburg, Germany
- 3. Department of Physics, University of Oxford, OX1 3QT, UK.
- 4. Bayer Pharma AG, Research & Development, Pharmaceuticals Wuppertal, Germany.
Description
The TWIK related acid-sensitive K+ channel 1 (TASK-1) belongs to the family of two-pore domain potassium (K2P) channels. It regulates resting membrane potential and is expressed in cardiomyocytes, neurons and vascular smooth muscle cells. Loss of function mutations in TASK-1 lead to primary pulmonary hypertension type 4 (PPH4) which is often fatal in mid-life (1). We have produced TASK-1 and determined structures of this protein alone and in complex with two highly potent inhibitors, BAY 1000493 and BAY 2341237, with EC50 values of 9.5 nM and 7.6 nM, respectively. We have used a two-electrode voltage clamp assay to measure the effect of mutations in TASK-1 and the effect of inhibitors. The native structure of TASK-1 also allowed us to map the six known disease mutations leading to PPH4.
Notes
Files
TASK-1_TEP_datasheet_v4.pdf
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Additional details
Related works
- Is part of
- https://www.thesgc.org/tep (URL)
Funding
- Wellcome Trust
- A UK Hub to Catalyse Open Target Discovery. 106169