Flying membrane protein aids cancer drug design

Researchers at Karolinska Institutet, Uppsala University and the University of Oxford, have used a new strategy to understand how specific enzymes can be shut down to stop cells from dividing. The method, published in Cell Chemical Biology, allows scientists to better target an enzyme to fight cancer.

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 is particularly difficult for membrane proteins, since they only function when incorporated into the cell lipid envelope, and often cannot be studied in isolation.

In a study published in Cell Chemical Biology this week, researchers from Karolinska Institutet, KTH, Uppsala University, and the University of Oxford, used a new strategy to find out how anticancer drugs bind to the membrane protein dehydroorotate dehydrogenase (DHODH), a new cancer target.

The groups of Sir David Lane and Sonia Lain at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet used native mass spectometry, a technique where a protein is gently removed from its normal environment and accelerated into a vacuum chamber. By measuring the time it takes for the protein to fly through the chamber, it is possible to determine its exact weight, which can, in turn, indicate whether the protein has bonded to another molecule and if so, what kind. The researchers used this highly accurate ”molecule scale” to see how drugs and lipids, the building blocks of the cell membrane, bind to DHODH.

"We saw that one of the drugs seemed to bind better to the enzyme when lipid-like molecules were present", says assistant professor Michael Landreh.

The team also found that DHODH binds a particular kind of lipid present in the cell’s power plant, the mitochondrial respiratory chain complex.

"This means the enzyme might use special lipids to find its correct place on the membrane", Michael Landreh explains.

To understand how lipids can help a drug recognize its target, the researchers worked with Dr Erik Marklund, group leader at the Department of Chemistry, Uppsala University, to build and compare computational models of free as well as membrane-bound DHODH.

"The study helps to explain why some drugs bind differently to isolated proteins and proteins that are inside cells. By studying the native structures and mechanisms for cancer targets, it may become possible to exploit their most distinct features to design new, more selective therapeutics", says Sir David Lane, professor at the Department of Microbiology, Tumor and Cell Biology.

The research was financed by:

The Swedish Research Council, The Foundation for Strategic Research, the European Research Council, and Karolinska Institutet.

Publication

"Lipids shape the electron acceptor-binding site of the peripheral membrane protein dihydroorotate dehydrogenase,"
Costeira-Paulo J, Gault J, Popova G, Ladds M.J.G.W., van Leeuwen IMM, Sarr M, Olsson A, Lane DP, Laín S, Marklund EG, and Landreh M
Cell Chemical Biology, online 18 January 2018
doi: 10.1016/j.chembiol.2017.12.012