Computer simulation of receptors reveals a new ligand-binding site

July 26, 2018, Ecole Polytechnique Federale de Lausanne

Using a computer simulation of an important receptor, EPFL scientists have discovered a novel binding site for natural ligands and drugs. The new site might be present on other receptors and can be exploited in novel treatments for multiple diseases.

Most biological processes in a cell go through receptors. These are specialized proteins that are activated when a ligand binds to them. Ligands can be all sorts of molecules (e.g. hormones, nucleic acids, neurotransmitters etc), and by binding receptors – and other proteins – they run complex processes such as cell maintenance, immune responses, genetics and others.

These normal cell processes involve complex "dominoes" of biochemical signals that are carried across the cell through protein-ligand interactions. On the other hand, they also lie at the core of a vast number of diseases. An entire branch of research known as "receptor pharmacology" is dedicated to exploiting these interactions with synthetic ligands (drugs), attempting to find ligand-binding sites that can exploited as a drug target.

Now, scientists led by Professor Horst Vogel at EPFL have developed a computer simulation of the widespread muscarinic acetylcholine receptor. Specifically, the scientists examined the M3 and M4 subtypes of the receptor, which are majorly involved in the function of the lungs (M3) and the central nervous system (M3 and M4).

The receptors belong to the large family of so-called "G " (GPCRs), which generally detect signals coming from outside the cells, such as light, hormones, or neurotransmitters. Upon activation, GPCRs change their structure in such a way that they can bind and activate other proteins inside the cell and ultimately turn on the appropriate process.

GPCRs are the target of more than a third of modern therapeutic compounds, meaning that finding new ligand binding sites can help design more efficient GPCR-targeted drugs.

The team used what are known as "molecular dynamics simulations", which is a method for simulating studying the physical movements of atoms and molecules in a computer. The method can reveal details down to the level of individual atoms, thus offering a high-resolution way to look at how various ligands bind on the receptor – and, more importantly, where.

The study revealed a new binding site on the acetylcholine receptors, which can be exploited pharmacologically to understand ligand binding and activation processes. When a ligand binds to the new site, it causes the entire site to expand. The site seems capable of binding small ligands and cause different effects to the receptor than the "main" ligand would.

Looking at more than 200 ligand-bound GPCR structures, the researchers discovered that most ligands bind the traditional ("orthosteric") sites on the receptors. However, one receptor that binds leukotriene (LTB4) and directs immune to sites of infection seemed to bind a "double" , which binds the new site discovered in the two acetylcholine receptors. The new site was detected in many others of the over 200 that the scientists examined.

The study shows that the new binding site might exist in other GPCRs, opening a new opportunity for GPCR drug discovery. "The study shows the power of computational methods to resolve in atomic detail central receptor-mediated signaling reactions," says Horst Vogel. "The challenging next step is to use computational methods to design novel compounds that would fit into the newly found binding sites to activate or deactivate the receptor in a defined mode and thus design novel medicines."

Explore further: Synthetic receptors can rewire cell functions and minimize side-effects

More information: H. C. Stephen Chan et al. Exploring a new ligand binding site of G protein-coupled receptors, Chemical Science (2018). DOI: 10.1039/C8SC01680A

Related Stories

Ties that bind, and can be untied

February 20, 2018

LMU researchers have developed a method that enables cell-surface receptors to be switched on and off at will. The technique promises to provide new insights into receptor functions and their effects on intracellular signaling ...

Tracing water channels in cell surface receptors

September 9, 2014

G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors in our cells, involved in signal transmission across the cell membrane. One of the biggest questions is how a signal recognized at the extracellular ...

CryoEM study captures opioid signaling in the act

June 22, 2018

Opioid drugs like morphine and fentanyl are a mainstay of modern pain medicine. But they also cause constipation, are highly addictive, and can lead to fatal respiratory failure if taken at too high a dose. Scientists have ...

Recommended for you

Custom-made artificial mother-of-pearl

December 10, 2018

Natural mother-of-pearl, such as mussels, is one of the hardest, most stable and stiff natural materials. Researchers have always been fascinated by it. The structure of mother-of-pearl is exquisite under the electron microscope; ...

Engineers repurpose wasp venom as an antibiotic drug

December 7, 2018

The venom of insects such as wasps and bees is full of compounds that can kill bacteria. Unfortunately, many of these compounds are also toxic for humans, making it impossible to use them as antibiotic drugs.

Researchers probe hydrogen bonds using new technique

December 7, 2018

Researchers at Carnegie Mellon University have used nuclear resonance vibrational spectroscopy to probe the hydrogen bonds that modulate the chemical reactivity of enzymes, catalysts and biomimetic complexes. The technique ...

Are amorphous solids elastic or plastic?

December 7, 2018

In a crystalline solid, the atoms form an ordered lattice. Crystalline solids respond elastically to small deformations: When the applied strain is removed, the macroscopic stress, as well as the microscopic configuration ...

Molecular insights into spider silk

December 7, 2018

Spider silk is one of the toughest fibres in nature and has astounding properties. Scientists from the University of Würzburg discovered new molecular details of self-assembly of a spider silk fibre protein.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.