Poster Presentation The 44th Lorne Conference on Protein Structure and Function 2019

Understanding the mechanisms of hERG channel gating and drug inhibition using cryo-EM (#183)

Carus Lau 1 2 , Mark Hunter 1 2 , Alastair G Stewart 1 2 , Michael Clark 3 , Eduardo Perozo 3 , Jamie I Vandenberg 1 2
  1. The Victor Chang Cardiac Research Institute, Sydney, NSW, Australia
  2. St Vincent’s Clinical School, University of NSW, Sydney, NSW, Australia
  3. Biophysical Sciences, The University of Chicago, Chicago, IL 60637, USA

The human ether-a-go-go related gene (hERG) potassium ion channel carries the major repolarising current in the heart. Loss-of-function mutations in the hERG K+ channel result in prolongation of the cardiac QT interval and increase the risk of life threatening cardiac arrhythmias such as torsade de pointes. These arrhythmias can also be caused by drug blockade of the ion conduction pathway which reduces the repolarising current. The first cryo-EM structure of the hERG K+ channel was published in 2017. However, much of the molecular details of gating and drug binding remain unknown. To further elucidate the mechanism of channel gating and drug inhibition of the hERG potassium ion channel we have purified hERG protein constructs that contain point mutations to stabilise different major gating states of the channel. We are also currently investigating the use of nanodiscs to further stabilise the channel to achieve better resolution.