Research shows protein movement is important
Researchers led by Professor of Chemistry Marcellus Ubbink have recently published a study in Proceedings of the National Academy of Sciences (PNAS) about the dynamics of an important redox enzyme. This work was accomplished thanks to an NWO VICI subsidy granted to Professor Ubbink.
Cytochrome P450cam is the archetype of a superfamily of cytochromes P450, which can be found in nearly all organisms and can be the catalyst for a broad range of reactions that reduce molecular oxygen. In humans these enzymes are involved in such processes as hormone production and the metabolism of foreign substances, such as medicines. P450cam can assume open and closed states. The open state binds the substrate, the closed state insulates the reaction from the environment so as to prevent reactive metabolites from escaping. In contrast with recent studies of the protein in a crystal state, this study shows that the enzyme stays in its closed state when the redox partner (the protein putidaredoxin) binds to P450cam. Paramagnetic NMR spectroscopy on the enzyme in a solution state made it possible to prove this. In this technique, the enzyme is studied on an atomic level using a lanthanide probe attached to the protein. The unpaired electrons in the probe have strong affinity with the nuclei of the protein, which is detected through nuclear magnetic resonance imaging (NMR).
The study emphasises the importance of looking not just at the structure, but also at the movement of proteins if we are to understand how they function. This fundamental shift in our perception of proteins is essential if we want to influence proteins, for instance when using enzymes in biotechnology or in the fine chemical industry, but also in the development of medicines. Using a computer to insert tiny molecules into static protein structures that can be developed into medicines is known as rational drug design. Disregarding the dynamic of the protein, however, is not very rational. Given the new insights in this field, this is likely to change soon. The paramagnetic NMR facility in Leiden, financed by NWO and Leiden University, offers new technology to make this movement in proteins visible.
(20 July 2015)