Karolinska researchers elucidate crystal structure of key asthma target

Researchers at Karolinska Institutet in Sweden have elucidated the crystal structure of a human membrane protein, LTC4 synthase, which has a major influence on the development of asthma.

In common with other membrane proteins LTC4 is extremely difficult to analyse, and previously only low resolution information has been available. The scientists believe that their work will enable the development of new and better drugs against inflammation in the pulmonary tract.

Asthma attacks are caused by an acute inflammatory reaction in the airways, a reaction that is largely due to action of LTC4 synthase. Many asthma drugs are targeted at blocking the downstream effects of the enzyme. However, not all patients respond to the existing medicines.

Now, Scientists at the Department of Medical Biochemistry and Biophysics have, with the help of the two EU networks EICOSANOX and E-Mep, elucidated the three dimensional structure of the LTC4 synthase at 2.0 Å resolution.

It is clear from the structure that the protein has three identical subunits, each of them consisting of four spiral structures that span the nuclear membrane. Also the exact position and characteristics of the active sites, where drugs molecules can bind, have been identified, making it possible to design drugs to block LTC4 synthase.

The research has wider significance as membrane proteins are one of the most important classes of drug targets. Until now there has not been detailed structural information on these proteins, making it difficult to fully understand their function.

The LTC4 study paves the way for the determination of structures of other human membrane proteins.