They found “weak spots” in one of the most frequently mutated proteins in cancer

They found “weak spots” in one of the most frequently mutated proteins in cancer

Team of Center for Genomic Regulation (CRG) from Barcelona and the Wellcome Sanger Institute in Cambridge (UK) in a study using Artificial Intelligence (AI) The “weak spots” are in the Kras protein, one of the most frequently mutated genes in the body cancer .

The study was published in the journal nature “comprehensively” identified allosteric control sites, which represent valuable therapeutic targets for drug development because they constitute secret vulnerabilities that can be used to control the effects of one of the most important causes of cancer.

Brochure It is one of the genes subject to the most mutations in many types of cancer and is found in one in ten human cancers, with a higher prevalence in severe types such as pancreatic or lung cancer.

The resulting protein has been compared to the Death Star from the Star Wars universe due to its spherical shape and “impenetrability”, and has been considered elusive since its discovery in 1982.

The only effective strategy for controlling Kras was to attack its allosteric communication system—molecular signals that operate through a key-and-lock remote control mechanism—and controlling it required a chemical compound or drug that could open an active site.

The CRG noted that after four decades of research, only two drugs have been approved for clinical use, and these work by binding to a cavity adjacent to the active site, triggering an allosteric conformational change in the protein that prevents activation.

CRG scientist Andre Faure emphasized that this study demonstrates a new approach to Systematic mapping of allosteric sites in complete proteins.

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The study authors mapped the divergent sites using a technique called “deep mutational scanning,” creating more than 26,000 variants of the Kras protein, changing only one or two amino acids at a time.

Researchers used artificial intelligence programs to analyze data, detect variation, and locate known or new therapeutic sites.

This technique showed that the Kras protein contains many more variant sites than expected, and that the mutations prevent interactions essential for the protein’s function, “suggesting that its activity can be broadly inhibited.”

The study provides the first comprehensive map of divergent sites ever obtained for an entire protein, and shows that with the right tools and techniques, “new vulnerabilities” can be discovered to modify many clinically relevant proteins that have historically been considered inoperable.

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