Liz Carpenter: Membrane proteins and drug development

Q: What are membrane proteins?

LC: Membrane proteins are large biological molecules imbedded in the surfaces of cells. All of the cells, the organelles within cells, and the nucleus of cells, are covered by a hydrophobic lipid bilayer which stops things going in and out of the cells. These proteins sit in the lipid bilayer and transport things in, move waste products out and send signals in and out of cells. This is the way the cells communicate with their outside world, their outside environment.

Q: So why does your line of research matter, why should we put money into it?

LC: There are two reasons. Firstly, many diseases are caused by mutations in these proteins, for example neurological diseases; depression, schizophrenia are the result of mutations in iron channels. Cystic fibrosis is a mutation in an ABC transporter protein; when the protein goes wrong they cause diseases. Secondly about 50% of all known small molecule drugs actually bind to membrane proteins on the surfaces of cells; if we want to design better drugs, if we want to aim to cure diseases, then we need to understand the actual molecular structure that drugs bind to and then we can develop better, improved drugs.

Q: What are the most important lines of research that have developed in the past 5 or 10 years?

LC: For a long time it's been possible to solve structures of soluble proteins - ones that sit in solution. For membrane proteins 5 or 10 years ago this was virtually impossible, there were about 10 structures. Over the last 5 years it's become possible to solve structures of membrane proteins from bacteria and a few human ones. Over the last year there have been very exciting developments in the field and large numbers of structures are starting to come out. We've gone from 2 or 3 structures a year to being able to produce 11 or 12 structures every year. These are structures of G protein coupled receptors; my own research looking at enzymes and ABC transporters. We're getting to a point now where we can look at structures that have come from humans which means we can actually use those structures to work to cure diseases.

Q: How do you determine the structure and the function of membrane proteins?

LC: First of all we have to extract the protein. These proteins sit in a very hydrophobic surface so we have to extract them using detergent, effectively washing up liquid. We pull them out of the membrane then we have to persuade them to line up in rows to form crystals - if you hit a single molecule with X-rays you don't get a diffraction pattern, it destroys the molecules. So we use the crystal to work as an amplifier. Once all these molecules are lined up together, we hit the crystal with X-rays and you get a diffraction pattern; we work backwards from the diffraction pattern to actually get the structure of the protein.

Q: Can you give us an example from your own current research?

LC: We've recently solved the structure of a very interesting protein called ZMPSTE24. It sits in the membrane of the nucleus of cells and its role is to process the nuclear lamins. These proteins that sit in the inside the nucleus of cells are involved in the division of cells and in binding to DNA in the cells. Our protein is necessary to process this protein so it's no longer attached to the membrane. When this goes wrong and it remains attached to the membrane, it leads to a number of diseases called laminopathies, including restrictive dermopathy which is a very unpleasant condition causing neonatal death, and progeria which is premature aging. By the time the child is 2 they have many symptoms you'd expect in an 80 year old and they usually die by their early teens as a result of heart disease. This is actually also possibly relevant for aging- normal aging within normal human beings. Mutations of ZMP or a lower level of production of this protein may lead to some of the adverse effects of aging in normal adults.

Q: How does your research fit into translational medicine within the department?

LC: The Nuffield Department of Clinical Medicine provides a unique environment for taking what is academic research, looking at structures and molecules and how small molecules bind to those structures, and translating that all the way into the clinic. Within the Structural Genomics Consortium we have a support structure that helps us to design not just molecules that bind and inhibit but also molecules that would be suitable candidates to be taken forward as drug targets. Within the NDM we have access to clinicians, to patient material which allows us to actually design efficiently small molecules so that, rather than purely academic research, we can take this forward into the clinic.