Nature: Tumor key protein structure was successfully resolved
August 07, 2015 Source: Bio Valley
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];In a study published in the international journal Nature , researchers from Argonne National Laboratory used high-specificity X-ray crystallography to analyze the protein structure of hypoxia-inducible factors (HIFs), hypoxia. Inducible factors are important regulators of tumor response to hypoxia, and this study may provide new ideas for finding new drugs to cut off the oxygen and nutrient supply of cancer cells to ultimately treat cancer.
Researcher Dr. Fraydoon Rastinejad pointed out that in this study we first unveiled the structure of the HIF1-α and HIF2-α complexes carrying the ARNT subprotein, which is the structure required to maintain HIF function; The visualization of the structure may help the researcher understand the ability of the drug to bind, and also help to develop new drugs to inhibit the tumor-promoting effects of HIFs.
HIF protein can regulate the expression of genes important for a series of tumor development. Regulating the activity of these genes is considered to be a promising method in cancer therapy. Many pharmaceutical companies are currently trying to find drugs that can inhibit the HIF pathway. It has been found that a drug candidate called PHDs can be combined, and PHD can modulate the activity of HIF protein. There are many inhibitors of PHD in a series of clinical trials for the current treatment of anemia, chronic kidney disease, stroke and cancer. According to Rastinejad, this study has provided some help for us to find drugs that bind HIF, rather than drugs that bind PHDs. Currently, we have identified five different groove-like structures in the structure of the HIF complex, all of which are It can be used to develop targeted small molecule inhibitors, and these drugs may inhibit the function of HIF by reducing the stability of HIF.
Drugs that inhibit HIFs may be used to treat solid tumors because solid tumors can grow beyond the blood supply to them, which can cause cancer cells to become hypoxic, thereby stimulating HIFs to open genes that regulate cancer cell survival pathways. Including angiogenesis, erythropoiesis, increased expression of anaerobic metabolic genes, and cancer metastasis; the synergy of all these processes can help promote tumor growth and its tolerance to drugs, ultimately reducing patient survival.
In the next step, the researchers will analyze a series of patient samples with HIF protein mutations. The researchers want to identify sites where HIF proteins are mutated and reveal the molecular mechanisms by which cells promote HIF dysfunction, while special mutations It often brings structural functional activity to HIFs to help them turn genes on or off. As researchers understand the structure, function, and regulatory mechanisms of HIFs, researchers may develop treatments for a range of diseases other than new cancer therapies, such as heart disease, fatty liver, diabetes, and inflammatory diseases.
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