Allotrope is moving

Today the Allotrope is moving to a new home at Scilogs.com. I have been a blogger on this network for a little over two years and it has been a pleasure to write here. I am grateful to the community and to Edward, the moderator, for this opportunity. But it is time to move on. On Allotrope's new home you can expect a lot more variety in the science writing that I do. The first post about how to stop aging related cognitive decline is already up. I hope you will come with me.

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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

A more powerful but less sensitive explosive

Pharmaceutical companies exploit a process called co-crystallisation to optimise the physical properties of drugs. Now scientists developing new explosives have done the same. As I report in The Economist, researchers from the University of Michigan have developed a method to lower the sensitivity of an explosive without losing its explosive power. 

Explosive power depends on two factors: detonation velocity (the speed at which the shock wave travels on explosion) and oxygen value (number of oxygen atoms per carbon atom). The higher the detonation velocity the more destruction it will cause. Oxygen value matters because when the explosion occurs carbon atoms within the explosive would like to react with oxygen atoms to form carbon dioxide. But because there is little time for carbon atoms to find oxygen from the air. Instead it has to rely on oxygen atoms within the explosive. Thus the closer the number of oxygen atoms per carbon atom is to two, the better the explosive.

One such explosive that has a higher detonation velocity and a better oxygen value than any of the commonly used explosives is CL-20. But it suffers from low sensitivity, which means that it will explode very easily if dropped or rubbed. This has meant that despite its early development it has mainly remained on the army barracks shelves.

Not anymore. Adam Matzger and colleagues have now made a hybrid explosive that has the same explosive power of CL-20 with reduced sensitivity. Find out how they made it here.

List of main references:

1. Matzger et al, Crystal Growth & Design, 2012
2. Matzger et al, Angew Chem Int Ed, 2009

Free image from here.