ESRF lightsource helps tailoring new treatments against asthma

Asthma affects 300 million people worldwide and, according to World Health Organization, it killed 255 000 people in 2005. Asthma attacks are caused by an acute inflammatory reaction in the airways, a reaction that is largely due to actions of LTC4 synthase (an enzyme which catalyzes a synthesis process). For this reason asthma medicines often aim to block the downstream effects of LTC4 synthase. 

However, there is a need for new pharmaceutical alternatives, since not all patients respond to the existing medicines. Thanks to the research partly carried out at the European Synchrotron Radiation Facility (ESRF), it is now possible to tailor new molecules that can block the LTC4 synthase. “I believe this breakthrough will speed up drug discovery against this disease”, explains Andrew McCarthy, one of the researchers in the team.

Scientists from the Karolinska Institute and the University of Stockholm in Sweden, together with colleagues from the European Molecular Biology Laboratory in France have solved the three dimensional structure of the LTC4 synthase at 2.0 angstrom resolution. The protein has three identical subunits, each consisting of four helical structures that span the membrane. The structure finally allows the exact position and characteristics of the active sites, where activating or blocking molecules can bind, to be identified.

The study of this protein at the ESRF proved a challenge for the team. The crystallization of membrane proteins is quite a complex process and even more challenging if they are human. So far only three human membrane proteins have been structurally characterized. The team carried out experiments at the ESRF to screen crystals several times before finally being able to determine the 3D structure.

LTC4 synthase overall structure. a) Left, front view of LTC4 synthase protomer in ribbon representation showing helices 1–5 in successive colouring. The entire LTC4 synthase polypeptide, except for the last residue (the last four in the GSH-complexed structure), can be traced in the electron density maps. Right, the homotrimer with protomers coloured orange, green and blue. Bound glutathione, indicating the position of the active site, is in ball and stick representation. Approximate membrane positions indicated by blue lines. b) Cytosolic view of the trimer, showing the position of the three active sites with loop 1 covering each binding pocket. Glutathione is shown in ball and stick representation together with modelled detergent (DDM). Image credit: D. Martinez Molina.

Membrane proteins- an open door to new pharmaceuticals

The new results can lead the way for the development of new and more effective medications against other diseases. Some 40% of the proteins of interest for pharmaceutical developments are membrane proteins.

Until now detailed structural information on these proteins has been absent, and therefore it has been difficult to fully understand their function. The present study is likely to lead the way for the determination of structures of other human membrane proteins. Unravelling the secrets of more membrane protein structures will help understand fundamental processes that take place in the cell membranes.

Reference

"Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase", Martinez Molina D, Wetterholm A, Kohl A, McCarthy AA, Niegowski D, Ohlson E, Hammarberg T, Eshaghi S, Haeggström JZ, Nordlund P, Nature AOP 15 july 2007.

For more information, please contact Montserrat Capellas ( email or +33 (0)476882663).