Missing 'key' could overcome drug discovery barrier

Missing 'key' could overcome drug discovery barrier

Illuminate newsletter header, Winter 2022
June 2022
Scientists have found a missing ‘key’ that unlocks critical channels responsible for potassium currents across cell membranes in a process that is essential for life.

Visualisation of potassium ions
Potassium ions (pink) traverse the pore of the
ion channel (green) through a ‘gate’ (teal) operated
by membrane lipids (yellow).

The discovery overcomes a major barrier to the development of novel drugs targeting a host of diseases, including some cancers.

The collaborative research team from WEHI and La Trobe Institute of Molecular Sciences (LIMS) have identified the ‘key’ to opening a molecular gate that controls currents of potassium ions across cell membranes.

Currents and channels

Ion currents transmit nerve signals in the brain and nervous system, regulate the heartbeat, and facilitate a host of critical cellular and tissue processes.

Dysregulation of the channels through which ions travel has been implicated in the development, progression and spread of cancers, as well as neurological, cardiac and kidney disorders. While ion channels are widely considered to be important druggable targets, it has proved difficult to exploit them.

Flow control

The team, led by WEHI’s Dr Jacqui Gulbis and Dr Katrina Black, and Professor Brian Smith, Dr Ruitao Jin and Sitong He from LIMS, discovered that the cell membrane in which ion channels are embedded held the missing ‘key’ that controls the flow of potassium ions.

“We found that specific fatty lipids from the membrane interact tightly with the channel to open a gate that allows potassium ions to pass through,” Dr Gulbis said.

“Not only is the gate in a different place than previously thought, it operates by a subtler and completely different process.”

The team made the discovery using sophisticated computer simulations, utilising millions of hours of high-performance computing with hardware typically used for gaming or mining bitcoin.

Drug discovery

“For over 20 years the search for pharmaceuticals that can exploit ion channels to treat disease has been in hiatus because drug companies were labouring under a gross misunderstanding as to how these ion channels work,” said Dr Gulbis.

“This new information on how potassium channels are controlled will open up new avenues and ideas for the rational discovery and design of new treatments.”

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