Solving a Parkinson's disease puzzle through protein design

EPFL researchers, in collaboration with UTSW and UCSD scientists, have developed a computational protein design approach, and used it to obtain the first ever high-resolution structure of an activated dopamine receptor in its natural cell membrane environment. The breakthrough will open up a new dimension in drug discovery for Parkinson's disease and perhaps other disorders. Dopamine is a neurotransmitter involved in everything from higher cognitive functions to motor control, motivation, arousal, reinforcement, and sexual gratification, the receptors it acts on have been a longstanding target for treating disorders like Parkinson's disease, which is caused by the degeneration of dopamine-using neurons that control movement. The problem is that for at least two decades, no-one has been able to "see" what a dopamine receptor looks like when it is activated by dopamine - at least not in high enough resolution to offer avenues for designing drugs that can target the receptors effectively. In a major collaborative study published in Nature, scientists from the lab of Patrick Barth at EPFL, with colleagues at UTSW and UCSD have now worked out the high-resolution structure of an activated form of a dopamine receptor in a native lipid membrane environment. "The native receptor is so misbehaved and its active form so transient that attempts at observing the receptor structure 'in action' have failed so far," says Barth. The way the scientists solved the problem was by combining state-of-the art computational allosteric and de novo protein design approaches developed by Barth's group allowing the researchers to engineer a highly stable but activated dopamine receptor whose structure they could then study and solve.