Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Membrane proteins are the gateways to the cell: many nutrients, ions, waste products, and even DNA and proteins enter and leave cells via proteins which are tightly controlled, maintaining the integrity of the cell. Drugs often target membrane proteins; therefore, understanding their molecular structure helps us design better drugs to cure diseases.

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.

Liz Carpenter

X-ray crystallography

Professor Liz Carpenter is part of the Integral Membrane Protein group at the Structural Genomics Consortium where they use X-ray crystallography to solve membrane protein structures. This information is used to improve and extend the available treatments for diseases such as heart disease and neurological diseases.

More podcasts related to Translational & Clinical

David Stuart: Structural biology and vaccines

Epidemics & Vaccines Translational & Clinical

The basis of an effective vaccine is that a pathogen is physically recognised by the immune system.

Kay Grunewald: Structural cell biology of virus infection

Epidemics & Vaccines Translational & Clinical

Understanding the entirety of a virus’ ‘life cycle’ requires an understanding of its transient structures at the molecular level. Using imaging techniques allows us to understand the communication between the virus and the components of the cell it is infecting, which can ultimately help to treat infectious diseases.

Jens Rittscher: Biological imaging

Translational & Clinical

Video microscopy aims to improve target discovery and drug development and to do so generates large volumes of data. Fluorescence labelling helps make intrinsic cellular functions visible and computational tools then enable analysis of these data sets to improve our understanding of cellular functions.

Sebastian Nijman: Pharmacogenomics

Translational & Clinical

In the context of cancer, genetic diversity means that we respond differently to various treatments. Pharmacogenomics sits at the intersection between genetics and drugs. Better understanding of the genetic landscape of cancer and the recent increase of targeted drugs allow us to better match patients with the best treatments, improving care.

Ian Pavord: Asthma

Translational & Clinical

Ian Pavord's research in to airway inflammation has resulted in mepolizumab being identified as an effective inhibitor of eosinophilic inflammation and asthma attacks. Mepolizumab is currently in Phase III clinical trials and if found to be effective could be a promising treatment for certain asthma patients.

Trudie Lang: The Global Health Network

Global Health Translational & Clinical

The Global Health Network is a successful and growing online science park comprised of varied research communities for different health research groups and cross-cutting health topics. It is built for the research and wider health community by researchers and public health practitioners themselves. It is a trusted source of quality information, education and research tools.

Najib Rahman: Respiratory Medicine

Translational & Clinical

Respiratory medicine encompasses a large number of common diseases like pneumonia, asthma, emphysema and lung cancer. Outcomes are currently relatively poor and the area of research is underfunded. Recent progress have been made towards personalising treatment, and Dr Rahman's research aims at improving patient care.

Chris O’Callaghan: Atherosclerosis & immunity

Translational & Clinical

Atherosclerosis is the most important cause of death worldwide. It is caused by the accumulation of both fatty material and immune cells. Over time, these set up an inflammatory reaction which causes a lot of damage to the blood vessel wall. Although we do have good therapies designed to lower the levels of fatty material, we haven’t any therapies specifically designed to target the effect of the immune system. Professor O'Callaghan's group is working towards developing such therapies.

Stefan Knapp: Development of chemical probes

Translational & Clinical

While drugs were initially developped by testing natural products directly in humans, the current approach is to use chemical probes. These are small chemical coumpounds that inhibit selected targets, avoiding side effects. Professor Knapp produces structures of molecular targets and makes them widely available. This will allow a faster and more cost effective development of new drugs.

Translational Medicine

From Bench to Bedside

Ultimately, medical research must translate into improved treatments for patients. At the Nuffield Department of Medicine, our researchers collaborate to develop better health care, improved quality of life, and enhanced preventative measures for all patients. Our findings in the laboratory are translated into changes in clinical practice, from bench to bedside.