Nav: Home

Designing and repurposing cell receptors

December 02, 2019

Called the "second secret of life", allostery is one of the most fundamental processes of biology and has been a central focus among scientists across the life sciences spectrum, from fundamental biology to drug development.

But what is allostery? In the never-ending dance of regulation inside the cell, allostery is the process by which proteins - and other biological molecules - can indirectly regulate the activity of other biomolecules like receptors.

The key here is "indirectly". Normally, proteins and other ligands will bind their target molecule, e.g. a receptor or enzyme, on a main region called the "active site". Once bound, the ligand triggers a biochemical domino that results in a particular effect.

But in allostery, ligands bind enzymes or receptors on sites other than the active site, and cause different effects. For example, allosteric binding can reduce or even stop the activity of a receptor altogether. The advantage here for fields like drug development is that allosteric ligands don't have to compete for the active site, but rather exerts their effects through a "side door".

Now, the lab of Patrick Barth at EPFL's Institute of Bioengineering has developed a computational method for predicting and even designing allosteric functions in proteins. Published in Nature Chemical Biology, the scientists show that their method can be used for predictably designing signaling functions into receptors that belong to the large family of G protein-coupled receptors (GPCRs).

The scientists began with molecular dynamics simulations, a computer technique that models the physical movements of atoms and molecules. Using this to model GPCRs, they were able to identify allosteric sites on the dopamine receptor, a GPCR in the nervous system that is activated by the neurotransmitter dopamine. Dopamine is involved in functions like motor control, motivation, arousal, reinforcement, reward, lactation, sexual gratification, and nausea.

They then applied a new method developed in the lab that can rapidly evolve in silico protein sequences for specific dynamic and allosteric properties. This allowed the scientists to design allosteric variants of a GPCR: receptors with small differences in the locations of their structure where ligands can bind allosterically.

These locations are called "microswitches" and can change the entire behavior of the receptor. "We were able to engineer novel amino-acid microswitches at these sites, which can reprogram specific allosteric signaling properties," says Barth.

The researchers produced no less than 36 variants of the dopamine receptor D2, which regulates cognitive flexibility in humans and is the main target for most antipsychotic drugs. In one case, the scientists were able to entirely repurpose the D2 receptor into a serotonin biosensor, essentially making it susceptible to an entirely new neurotransmitter.

After binding serotonin, the redesigned receptor showed potent signaling responses that matched the predictions that the scientists made using their computational method. This accuracy wasn't only limited to the one variant; the researchers were able to predict the effects of more than a hundred known mutations on the signaling activities of several GPCRs.

Finally, it is important to note that the new method afford what chemists and bioengineers call "rational design": a strategy that uses computer modeling to predict how the new molecule's structure and dynamics will affect its behavior.

"So far, protein design has mostly focused on engineering stable protein structures and interactions lacking dynamics," says Barth. "Our work demonstrates the development and validation of the first computational approach that enables the prediction and rational design of protein allosteric dynamic functions; it sets the stage for designing signaling receptors with precise functions for cell-engineering approaches and predicting the effects of genetic variations on protein functions for personalized medicine, as well as designing new allosteric proteins and better drugs from scratch."
Other contributors

Baylor College of Medicine


Chen K-Y, Keri D, Barth P. Computational design of G Protein-Coupled Receptor allosteric signal transductions. Nature Chemical Biology 02 December 2019. DOI: 10.1038/s41589-019-0407-2

Ecole Polytechnique Fédérale de Lausanne

Related Dopamine Articles:

Significant differences exist among neurons expressing dopamine receptors
An international collaboration, which included the involvement of the research team from the Institut de Neurociències of the UAB (INC-UAB), has shown that neurons expressing dopamine D2 receptors have different molecular features and functions, depending on their anatomical localization within the striatum.
How dopamine drives brain activity
Using a specialized magnetic resonance imaging (MRI) sensor that can track dopamine levels, MIT neuroscientists have discovered how dopamine released deep within the brain influences distant brain regions.
Novelty speeds up learning thanks to dopamine activation
Brain scientists led by Sebastian Haesler (NERF, empowered by IMEC, KU Leuven and VIB) have identified a causal mechanism of how novel stimuli promote learning.
Evidence in mice that childhood asthma is influenced by the neurotransmitter dopamine
Neurons that produce the neurotransmitter dopamine communicate with T cells to enhance allergic inflammation in the lungs of young mice but not older mice, researchers report Nov.
Chronic adversity dampens dopamine production
People exposed to a lifetime of psychosocial adversity may have an impaired ability to produce the dopamine levels needed for coping with acutely stressful situations.
Blocking dopamine weakens effects of cocaine
Blocking dopamine receptors in different regions of the amygdala reduces drug seeking and taking behavior with varying longevity, according to research in rats published in eNeuro.
How chronic inflammation may drive down dopamine and motivation
A new computational method will allow scientists to measure the effects of chronic inflammation on energy availability and effort-based decision-making.
Dopamine regulates sex differences in worms
Dopamine is responsible for sex-specific variations in common behaviors, finds a study of worm movements published in JNeurosci.
Dopamine conducts prefrontal cortex ensembles
New research in rodents reveals for the first time how dopamine changes the function of the brain's prefrontal cortex.
Dopamine modulates reward experiences elicited by music
New study in Proceedings of the National Academy of Science reveals causal link between dopamine and human reward response to music listening.
More Dopamine News and Dopamine Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Clint Smith
The killing of George Floyd by a police officer has sparked massive protests nationwide. This hour, writer and scholar Clint Smith reflects on this moment, through conversation, letters, and poetry.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Producer Tracie Hunte stumbled into a duet between Nina Simone and the sounds of protest outside her apartment. Then she discovered a performance by Nina on April 7, 1968 - three days after the assassination of Dr. Martin Luther King Jr. Tracie talks about what Nina's music, born during another time when our country was facing questions that seemed to have no answer, meant then and why it still resonates today.  Listen to Nina's brother, Samuel Waymon, talk about that April 7th concert here.