It is now possible to determine the molecular structure of membrane proteins, previously difficult to characterize, offering better possibilities of developing pharmacological inhibitors for treating cancer and other diseases.
Turning off enzymes that are important for the survival of growing cells is a promising strategy to fight cancer. But to be able to shut down only one specific enzyme out of thousands in the body, drugs have to be tailored to exactly fit their target. This has been particularly difficult for membrane proteins, as they only function when incorporated into the membrane lipid bilayer, and often cannot be studied in isolation.
In the new paper, researchers from the groups of David Lane and Sonia Laín (Karolinska Institutet/SciLifeLab) and their collaborators at Uppsala University, KTH Royal Institute of Technology and University of Oxford presents a novel approach for determining membrane protein structures, which combines native mass spectrometry with advanced computer simulation.
By applying the method to the peripheral membrane protein and key anti-cancer target dehydroorotate dehydrogenase (DHODH) located at the mitochondria, the team is able to obtain detailed insights into the structural relationship between membrane lipid and substrate binding to the enzyme.
“To our surprise, we saw that one drug seemed to bind better to the enzyme when lipid-like molecules were present,” says assistant professor Michael Landreh (Karolinska Institutet), who led the study.
The team also found that DHODH binds a particular kind of lipid present in mitochondrial respiratory chain complex, an important system for cellular energy production.
“This means the enzyme might use special lipids to find its correct place on the membrane,” Michael Landreh explains.
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