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 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.