Cancer: A New Technique Uncovering Another Mystery of Life: Allosterism

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Four years before winning the Nobel Prize for Medicine, French biologist Jacques Monodo Standing in a colleague’s lab one night in 1961, with a weary face and after a few minutes of silence, declared: “I think I’ve discovered life’s second secret.” asked by his partner, microbiologist Agnes Ullman if i want a glass of whiskey, After the third glass, Monod explained that he had witnessed an amazing phenomenon: Proteins, the true protagonists of living matter, had a sort of hidden button that changed their function. Monod even invented a term to define that amazing transformation: allosterism. More than half a century later, a team of scientists in Barcelona has discovered a method to identify those secret buttons. The authors argue that the system could “revolutionize” drug discovery against cancer and other diseases.

Inside human cells is a recipe book for making proteins – DNA, the first secrets of life: the keratin of the skin, the collagen of the bones, the myosin of the muscles, the hemoglobin of the blood. It’s easy to imagine simple molecules, such as the one Jacques Monod drank in whiskey, that have two carbon atoms, six hydrogen atoms, and one oxygen: C₂H₅OH. On the other hand, proteins are often incomprehensible chemical monsters. The formula of hemoglobin is C₂₉₅₂H₄₆₆₄N₈₁₂O₈₃₂S₈Fe₄, In the lungs, it binds to large amounts of oxygen, changing its three-dimensional structure to make it easier to bind more oxygen elsewhere. This is an example of allostericism, a Greek root word that can be translated as “Another Structure”,

A team from the Center for Genomic Regulation (CRG) in Barcelona has now uncovered this second secret of life. biologist Julia Domingo He likens the Proteus to a microscopic car, which can be started with an ignition key, but also via a “remote control” hidden in the bodywork. “It’s hard to know where to look for them. Our method is to take the car and scrap it. We take out all the fragments and analyze them one by one”, explains Domingo, who is now at the New York Genome Center (USA).

Spanish biologist Julia Domingo and South African bioinformatician André Faure.
Spanish biologist Julia Domingo and South African bioinformatician André Faure.Julia Domingo

The new technology creates thousands of versions of the same protein with one or two mutations, and automatically examines their properties in living cells. The result is a map of predicted secreted buttons, so-called allosteric sites, that can be used to modify the function of proteins through drugs. CRG team led by British biologist ben lehnerPublishes its method this Wednesday in the magazine NatureBest world science showcase.

Julia Domingo gives an example. In 95% of pancreatic cancer cases, proteins called KRAS are mutated, which for decades are believed to be immune to drugs, because they lack obvious binding sites. The authors are already applying their method to these proteins, and others of equal importance, to attempt to find their secret buttons. “Generally speaking, drugs are designed with a very random and serious process. Companies start with hundreds of thousands of candidates, without really knowing what they are doing”, explains Domingo. “Our aim is to map allosteric sites, to know what properties the drugs should have. Instead of starting blindly, we will know where to direct the drugs”, celebrates Domingo.

Proteins usually have a clear starter key, the active site, which can act like a switch. The major problem for medicine is that the active sites of different proteins are very similar, so drugs targeting these sites can alter many proteins, causing serious side effects. Allosteric drugs, directed at secreted buttons, are more specific, explains Domingo, the first signatory of the study with South African Bioinformatics. Andre Faure and German biophysicist jorn schmeidel,

“It is the holy grail of pharmaceuticals”

Julia Domingo, biologist

Several biotech companies have launched in recent years to discover these hidden doors to proteins. American company Riley TherapeuticFor example, has received nearly $1,000 million to investigate potential allosteric drugs against certain tumors, such as breast cancer. “This is the holy grail of drugs”, declared Julia Domingo, born 31 years ago in Barcelona.

One of the main scientific achievements of 2021 was that an artificial intelligence system from Google’s DeepMind company, managed to predict with unprecedented accuracy the structure of almost all the proteins that make up a human. The CRG scientists believe that their new method could be used to measure the effects of millions of mutations in thousands of proteins. An artificial intelligence system, they speculate, could use this vast amount of data to make another huge leap forward: predict the function of a protein from its DNA recipe. In the authors’ opinion, this predictive ability would be “revolutionary” in the development of medical treatments.

spanish biophysicist Victor Munozzifrom the University of California at Merced (USA), appreciates the new method. “This is a tool that can be useful for identifying regions in proteins that are likely to be targets of a drug,” he says. Munoz, however, is more cautious. The researcher also uses the example of a car. If the axle connecting the engine to the wheels is modified, the vehicle stops working, he says. This would be an allosteric change. “If you remove a wheel, the car doesn’t even work, but that’s because it’s missing a piece, it’s not like you touched something that was dynamically attached,” Munoz details.

In the opinion of the biophysicists, the new method could reveal allosteric sites that are not actually there. “They mutate extensively and see that someone has disabled the car, but they don’t know if a wheel is missing or the axle has been modified. You need more detailed information. You can use this method to identify a potentially interesting region, but then it will take a lot more work to confirm it”, says Munoz, Director Center for Cellular and Biomolecular Machines from University of California.

chemistry Nuria Campillo directing Athenia Biotech, a company dedicated to pharmaceutical research and development, promoted by the High Council for Scientific Research. Campillo believes the new method is “an impressive piece of work, a very elegant way of identifying allosteric sites.” In his opinion, the tool will “facilitate the discovery of more effective and safer drugs”. The second secret of life is no longer so secret.

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