Solving a Parkinson's disease puzzle through protein design

Date:
June 11, 2020
Source:
Ecole Polytechnique Fe'de'rale de Lausanne
Summary:
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.



FULL STORY ========================================================================== 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.

The EPFL team created a receptor with artificial building blocks such as activating switches and de novo binding sites, which replaced unstable, structurally disordered, and inactivating regions of the native receptor.

"This hybrid functional/de novo computational protein design approach is powerful, as it enabled us to create a receptor with considerably enhanced activity and stability while recapitulating key native functionalities
such as dopamine-mediated intracellular signaling and binding," says
Barth.

The success was also made possible by using high-end lipid reconstitution techniques and cryo-electron microscopy, overcoming obstacles in previous studies that attempted to determine the receptor's structure using X-ray crystallography and by keeping the receptor inside detergents.

The problem is that detergents are very poor mimics of the cell's
lipid membranes where receptors like the dopamine one are naturally
located. Also, detergents have a reputation of distorting and even
inactivating receptors, which doesn't help when attempting to see what
they look like in action. "This represents the first atomic-level membrane-receptor structure determined in a native lipid bilayer,"
says Barth.

"The breakthrough will enable improved drug discovery efforts against,
for example, Parkinson disease," he adds. "But it also sets the stage
for broadly applying functional and de novo protein design approaches
to accelerate the structure determination of challenging protein targets
and create proteins with novel functions for a broad range of therapeutic
and biotechnological applications."

========================================================================== Story Source: Materials provided by
Ecole_Polytechnique_Fe'de'rale_de_Lausanne. Original written by Nik Papageorgiou. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Jie Yin, Kuang-Yui M. Chen, Mary J. Clark, Mahdi Hijazi, Punita
Kumari,
Xiao-chen Bai, Roger K. Sunahara, Patrick Barth, Daniel
M. Rosenbaum.

Structure of a D2 dopamine receptor-G-protein complex in a lipid
membrane. Nature, 2020; DOI: 10.1038/s41586-020-2379-5 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200611094114.htm

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