Most drugs work through the organs that surround the body’s cells. A study by researchers at Karolinska Institutet in Sweden has now documented the structure and mechanism of MGST2, a membrane enzyme that, among other things, plays a role in inflammation and breast cancer. The study, which is published in the journal Nature Communication, contribute significantly to the future development of drugs.
Our cells are all enclosed in a ball full of fat. The organ-like cells, the organelles, are also surrounded by organs. Involved in the internal and external organs of the cell are proteins that regulate a large number of vital functions. Nearly half of the drugs are effective through member proteins, such as enzymes, receptors and transporters.
Researchers at Karolinska Institutet have now, with the help of X-ray crystals, molecular dynamics simulations and biochemical methods, discovered the structure and 3D mechanism of an important enzyme rooted in the cell’s nuclear organ. .
The membrane enzyme MGST2 (Microsomal Glutathione S-Transferase 2) is a motor of a biochemical process that causes oxidative stress and the formation of oxygen radicals and, subsequently, DNA damage and cell death.
“Membrane proteins are difficult to study and it is a miracle that we have discovered the crystal structure for high-resolution MGST2,” said the first author in the study Madhuranayaki Thulasingam, a researcher at the Department of Biochemistry and Biophysics, Karolinska Institutet. “One of the findings of the study is that MGST2 is made up of three action units that are controlled in an unusually solemn manner. All three units are engaged in coordinated movements, taking advantage rather than performing the action of the enzyme as one functional unit at a time. “
MGST2 belongs to a larger family of enzymes that control the production of prostaglandins and leukotrienes, identifying molecules that regulate fever, pain and inflammation in the airways, joints, heart, and blood vessels.
The results provide valuable information on the molecular regulation of other members of the enzyme family, many of which are important targets for future drug development.
“We hope that our results can contribute to the development of drugs for many diseases characterized by increased synthesis of oxygen radicals and cell death, such as chronic inflammation, cancer and the side effects of radio- and chemotherapy,” says the study. principal investigator Jesper Z. Haeggström, professor at the Department of Biochemistry and Biophysics, Karolinska Institutet.
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The study was supported by grants from the Swedish Research Council, the Novonordisk Foundation and the Karolinska Institutet. Conflicts of interest are not reported.
Published: “Crystal structures of human MGST2 exhibit synchronous conformal changes governing catalysis” Madhuranayaki Thulasingam, Laura Orellana, Emmanuel Nji, Shabbir Ahmad, Agnes Rinaldo-Matthis, Jesper Z. Haeggström. Nature Communication, online 19 March 2021, doi: 10.1038 / s41467-021-21924-8.
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