Cryo-EM leads way to new anti-addiction drugs
Image: A serotonin transporter bound with ibogaine (lime spheres) has outward-open, closed and inward-open shapes.
Using cryo-electron microscopy, US-based researchers have revealed the three major shapes of the serotonin transporter, a protein in the brain linked to anxiety and depression.
By studying how the protein binds to anti-addiction drug, ibogaine, also known for its hallucinogenic effects, Professor Eric Gouaux from Oregon Health and Science University Vollum Institute and a Howard Hughes Medical Institute investigator, and colleagues, determined the structure of the serotonin transporter in its outward-open, closed and inward-open shapes.
The researchers hope that the latest results will open the door to developing anti-addiction medications without hallucinogenic properties.
"[These results] mean we can target different states of the transporter to modulate its activity," says Gouaux. "It opens up new thinking of how you might come up with novel molecules to bind to the transporter."
"There's a real need to develop molecules that have these anti-addictive properties," adds Gouaux's colleague, Dr Jonathan Coleman from the OHSU Vollum Institute.
Influencing virtually all human behaviours, serotonin regulates the activity of the central nervous system as well as processes throughout the body, from cardiovascular function to digestion, body temperature, endocrinology and reproduction.
The serotonin transporter acts as a molecular pump for serotonin, recycling the neurotransmitter following neuronal signalling.
Serotonin shapes neurological processes including sleep, mood, cognition, pain, hunger and aggression.
In 2016, Gouaux led a team that revealed the structure of the serotonin transporter, providing insight into how the antidepressants, citalopram and paroxetine, interact with and inhibit the transport of serotonin.
The latest results extend this research by showing the transporter's major conformations.
As the researchers point out in Nature, images were acquired using a FEI Titan Krios equipped with a Gatan Image Filter operating at 300 kV or an Arctica TEM at 200 kV.
In each case, a Gatan K2 Summit direct electron detector was used to record movies in super-resolution counting mode.
"Most antidepressant drugs bind to the outward-open conformation, [but] our study shows ibogaine can bind to the inward state," highlights Dr Dongxue Yang from Gouaux's lab.
"It provides many more avenues to design small molecules with anti-addictive properties," adds Coleman.
Research is published in Nature.