December 9, 2019

Understanding Cell Surface Receptors for Better Pharmacuticals

Cell surface receptors are gateways into living cells. They control how a cell ‘feels’ its environment and they activate ‘switches’ for cellular response. The fact that they are located on the outside of a cell and that they are the master regulators of many cellular processes makes them an attractive target for therapeutic molecules. Now researchers at Monash University are using high-powered electron microscopy and supercomputers to create detailed images of an important class of cell surface receptors, with the prospect of identifying new and/or better drugs.

Cell surface receptors take signals from outside the cell – for example, drug molecules that bind to the receptor protein – and trigger a cascade of biochemical events inside the cell.

G protein-coupled receptors are the largest family of cell surface receptors, numbering around 800 different types. Around one-quarter of all medications interact with these cell surface receptors, yet only a relatively small fraction of this family of receptors is currently used as drug targets.

“There’s still a lot of interest in whether there are other G protein-coupled receptors that could be manipulated to become useful therapeutics,” says Professor Patrick Sexton, from the Monash Institute of Pharmaceutical Science.

Sexton and colleagues are studying around twenty different types of G protein-coupled receptors – some well known, some less well studied – and the roles they play in diseases such as diabetes, obesity and cardiovascular disease.

One receptor of particular interest is the glucagon-like peptide 1 receptor, or GLP-1 receptor, which is already targeted by a class of diabetes drugs but is also important in regulating appetite. The research team have discovered that different ligands binding to this receptor can lead to very different cellular signals being released inside the cell.

To understand how and why this happens, they’re using a technique called cryogenic electron microscopy to study the receptor structure, both by itself and with potential drug molecules bound to it.

The proteins being imaged are first vitrified – frozen in such a way as to not produce ice crystals – then the electron microscope takes millions of images of the receptors. These images are then combined to provide a clear, three-dimensional image of the receptor structure.

“You need to experimentally determine where these drug molecules bind and this technique is able to do that now, and I think that’s where the excitement is,” says Dr Matthew Belousoff, also from Monash University. But that process takes a huge amount of computational power, which is where MASSIVE comes in,

“With the aid of these large supercomputer clusters, where we’re not waiting weeks and weeks for the computers to finish calculation: we’ve got resources enough to understand sometimes within a couple of days how the drug looks.”

Using the power of high resolution cryo electron microscope coupled with the computing resources of MASSIVE, we can now directly image drug interactions with important pharmaceutical targets. The figure shows the binding of an ‘antagonist’ drug (grey sticks) bound to its target, a G-coupled protein receptor.