Nature: Whole process of “E3 Ubiquitin Ligase” defends cancer cells

Nature: Whole process of “E3 Ubiquitin Ligase” defends cancer cells.   Cancer cells are called “liar cells”. They can evolve rapidly, pretend to be dormant and survive the attack of drugs. Therefore, traditional “small molecule” drug therapies can no longer defend against cunning cancer cells. Some are urgently needed. New technologies support the rapid development of new drug research and development in the future.

Recently, the scientific research team of the Max Planck Institute published an article entitled “Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly” in the top journal “Nature”. The study found that the human body There is a “SCF–RBR E3–E3” ubiquitin ligase super assembly in the cell, which can connect ubiquitin to the F-box protein target, thereby resisting tumorigenesis. At the same time, the researchers also developed a The new cryomicroscope visualizes this new anti-tumor therapy for the first time.

This new therapy uses a family of human enzymes called “ubiquitin ligases” found in human cells. This enzyme is the third enzyme (E3) in the protein ubiquitination pathway, which can accelerate the chemical reaction at the cellular level in the human body, strategically target the disease-causing protein, and cause it to degrade and die.

So far, almost every large pharmaceutical company is at various stages of developing this new technology. Among them, Arvinas’s world’s first protein degradation targeted chimera (PROTAC) drug “ARV-110” for the treatment of prostate cancer is a kind of use of E3. One end of the drug molecule can bind to the target, and the other end is bound to E3 ubiquitin ligase. The target is labeled with ubiquitin ligase, and then the target protein is transported to the cell’s proteasome for degradation.

It is well known that the SKP1-CUL1-F-box (SCF) complex can play a key role in a variety of cellular processes by degrading specific substrates, but many ubiquitin-modified cullin-RING E3 ligases (CRL) and RBR-type E3 Ligase (ARIH1) does not work alone in the human body. They usually form an “E3-E3 super assembly” to resist the enemy.

In this latest study, researchers analyzed the cullin-ring E3 ligase (CRL) in the E3 ubiquitin ligase complex “SKP1-CUL1-F-box (SCF)” family and found that the F-box protein can By participating in the co-evolution of the SCF ligase and ARIH1 ligase complex, the formation mediates the specific recognition of ubiquitinated protein substrates. Therefore, based on this active specific chemical probe, the researchers developed a new type of cryo-electron microscope (cryo-EM) to visualize the process of E3-E3 ubiquitination.

The imaging results showed that the E2 enzyme “human ubiquitin-conjugating enzyme E2C-binding protein E2L3 (UBE2L3)” was first ligated to ubiquitin, then transferred to the catalytic cysteine ​​of ARIH1, and finally ubiquitin was transferred to the SCF E3 ligase On the bound substrate, this is the entire E3-E3 ubiquitination process.

At the same time, the researchers also observed from the imaging results that the SCF–RBR E3–E3 super assembly connects ubiquitin to the F-box protein target. The disorder of the protein degradation process involved in this F-box protein can lead to tumors. , So researchers can design cancer drugs for F-box protein.

This is the first time scientists have actually seen atomic-resolution photos of ubiquitin ligase at work. This may be a new starting point in the field of innovative drug development. Let us wait and see and witness the miracle happen together.

(source:internet, reference only)

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