蛋白质 z-bo 2020-10-26 425

　　Proteins are an indispensable part of living cells. Proteins are combined with large polymer complexes (a combination of proteins) to perform specific functions together. Many cancer research focuses on finding inhibitors of these protein complexes. Such proteins include kinases such as mTOR and ATR and tumor overexpressing enzymes such as telomerase.

　　There are several proteins (called chaperone proteins and chaperone proteins) that can build these protein complexes into cells, and inhibition of this assembly process is currently being studied as an anti-cancer strategy. You can compare kinases and enzymes (such as mTOR, ATR, and telomerase) with buildings under construction. Chaperone proteins (such as HSP90) and chaperone proteins (such as R2TP) are building machines. Current evidence suggests that targeting RUVBL1-RUVBL2 can treat cancer. UVBL1-RUVBL2 are the energy engines included with R2TP. This allows researchers in the DNA damage response research group of the Spanish National Cancer Research Center (CNIO) to use powerful cryo-electron microscopy tools to determine the mechanisms that control RUVBL1 and RUVBL2. The research was published in the journal "Science Advances".

　　"As mentioned earlier, the polymer complex research team used cryo-electron microscopy to determine the high-resolution structure of R2TP in the DNA damage response. In this study, CNIO researchers observed how cells design R2TP so that its chaperone protein HSP90 contacts the protein it acts on. The 2TP complex has an energy engine, a ring composed of ATPaseUV BL1 and RUV BL2, which can use the energy released by ATP hydrolysis to generate ADP. In this energy production mechanism, ATPase captures intracellular ATP and continuously releases ADP as waste and energy. Scientists found that in the circuit formed by RUVBL1 and RUVBL2, the path to the ATP binding site is completely blocked, and ATP or ADP stays in the circuit, thereby hindering energy exchange and motor operation. done. The question is how to use the energy required to assemble protein complexes.

　　By observing the R2TP system with a cryo-electron microscope, the researchers found the answer. "We found a region in RUVBL2 that serves as a control entry for ATP and ADP. Protein channels. This process requires the use of energy provided by ATP. The key to regulating the opening of this gate is the R2TP required for ATPaseRUVBL2 and mTOR assembly. The interaction between the components. ""

　　The study of protein structure and dynamics, that is, understanding the interaction between proteins is necessary for biological functions and experimental observations, whether it is a calculation method or not, it is always difficult. However, the use of cryogenic microscopy to study protein-polymer complexes is one of the focuses of CNIO's structural biology project. As mentioned in Nature a few months ago, it completely changed the way of observing and understanding proteins. how to work. A thorough understanding of the process of determining how to construct polymer complexes will help discover new cancer treatment strategies based on inhibiting protein assembly. Several studies have shown that inhibiting RUVBL1-RUVBL2ATPase has therapeutic potential in cancer treatment.

　　CNIO's Llorca and Laurence H are from the University of Sussex, UK. The latest research published in the journal Science Advances by a team led by Pearl's team can help accelerate progress in this field.