EU researchers decode structure of vital proteins

A team of EU-funded researchers has worked out the structure of a membrane protein, which is responsible for transmitting messages from the outside of the cell to the inside. Membrane proteins
are involved in the development of a number of diseases, and as such they are a major target for drug development.

The study, which was published online by the journal Nature, was funded by the Sixth Framework Programme IMPS (Innovative tools for membrane structural proteins) project. Meanwhile, the
European Commission announced that it is to fund two further projects on membrane proteins under the Seventh Framework Programme (FP7).

The protein studied by the IMPS team is a G protein-coupled receptor (GPCR). There are around 700 GPCRs in humans, making them the largest family of cell membrane proteins. Their job is to
sense molecules outside the cell and trigger reactions inside the cell. These receptors play a role in controlling blood pressure, heart rate and digestive processes. Furthermore, they allow us
to process light and smells and regulate our behaviour, mood and immune response. Around half of all modern drugs target GPCRs, and they are the subject of intensive research by pharmaceutical

Over recent decades, scientists have succeeded in increasing our understanding of GCPRs. However, these proteins’ low abundance and instability in the laboratory have hindered attempts to work
out how the structure of the proteins influences the way they transmit signals across the cell membrane.

In this latest piece of research, the international team of scientists used the latest techniques in protein expression crystallisation and microcrystallography to obtain a high-definition
crystal structure of the human beta 2 adrenoreceptor, which plays important roles in cardiovascular and pulmonary physiology.

‘This is a case of basic research, which after many years has finally paid off,’ said Dr Gebhard Schertler of the UK’s Medical Research Council, who has been studying GPCRs for many years. ‘Our
development of high brilliance micro-crystallography techniques in collaboration with the European Synchrotron Facility has played an essential role in this effort.

‘The methodology, involving the expression and stabilisation of the receptor followed by high brilliance micro-crystallography, provides a good strategy for solving the structure of many GPCRs
and other clinically important membrane proteins.’

The two new projects slated for funding under FP7 are set to receive around ¿11 million each, and will start in 2008. The EDICT
(European drug initiative on channels and transporters) project aims to characterise the structure of several membrane superfamilies in humans and pathogenic micro-organisms, covering a wide
range of human diseases and addressing global health issues.

The NeuroCypres (Neurotransmitter Cys-loop receptors (CLRS): structure, function and disease) project, will focus its efforts on a single class of physiologically important channels called
Cys-loop receptors. These have been identified as targets for drugs to treat a variety of diseases, including Alzheimer’s, Parkinson’s, certain forms of epilepsy and anti-smoking compounds.

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