The magical role of the doormen

Half of all pharmaceuticals work because of a family of proteins that sit on the boundary of cells in the human body. This year’s Nobel prize in chemistry was awarded to Robert Lefkowitz and Brian Kobilka for their work on a family proteins called G protein-coupled receptors (GPCRs). Nearly every function of the human body from smell and sight to heart rate modification is dependent on GPCRs. Dr Lefkowitz and Dr Kobilka have helped us understand their chemical structure and mode of action to help create better means of manipulating them to our advantage.  

Robert Lefkowitz
Credit: Wikipedia

Embedded in the fatty membranes of cells, GPCRs act as doormen to a mansion. They detect chemical signals that reach the cell and convey messages through creation of G proteins inside the cell. These G proteins that take on the role of maid servants then act on the message by activating the necessary response.

But this was not known until the 1960s. All that was known then was that hormones communicated with cells in someway but no one knew how. Dr Lefkowitz started probing these hormones by attaching radioactive isotope Iodine on to them. This revealed that the cell membrane had special proteins that acted as telegraph operators relaying information from one side to the other. He was able to identify one class of these proteins called beta-2 adrenergic receptors. These are interesting because they are now implicated in responding to the neurotransmitter adrenaline known to control the fight-or-flight response.

In 1984 when Dr Kobilka arrived in Dr Lefkowitz’s lab, the lab was working on duplicating the gene sequence that made beta-2 adernergic receptors. If they could, then it would enable them to know more about the role of these proteins and how they work. When they eventually managed to do it, after a lot of failed attempts, they realised that this protein was very similar to rhodopsin, a protein that sits in the retina and is responsible our perception of light. Rhodopsin was known to activate G-proteins in the cell and that is it was thought that these could be a class of proteins, now known as GPCRs.

We now know that human body has about 800 GPCRs splayed across different cells performing some of the most critical functions. About half of these are predicted to be pharmaceutically useful, but less than 10% of that have drugs targeting them today. A major hurdle in creating pharmaceuticals for them is because little is known about the chemical structure of these proteins.

Brian Kobilka
Credit: Stanford

A way to shine light on the chemical nature of proteins is by using X-ray crystallography. To do that though, a protein first needs to be crystallised (lots of molecules arranged in a regular fashion in a tiny space). Proteins, in general, and GPCRs, particularly, are notoriously difficult at doing that. Of the 63 million proteins registered in the database of the Chemical Abstracts Service, only 600 have comprehensive structural data available for them. But in 2007 after decades of work Dr Kobilka managed to tame the beta-2 adrenergic receptors and published its structure in Nature.

The pharmaceutical industry has only started scratching the surface when it comes to designing drugs that affect GPCRs. And that has been the result of many decades of efforts by structural biologists and medicinal chemists in academia and industry. The work of Dr Lefkowitz and Dr Kobilka has opened the possibility of better understanding what one scientist calls cell biology—an alien world that has the most profound impact on humanity.

Main references:

1. Rasmussen et al, Nature, 2007
2. Buchen, Nature, 2011
3. Sansom, Chemistry World, 2010