Recently, a research team composed of the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences and the United States, Singapore and other researchers has successfully solved the technical bottleneck of folic acid receptor expression, purification and crystallization, and successfully analyzed folate / folate The crystal structure of the receptor FRα complex systematically illustrates the specific binding pockets and precise interaction sites of folic acid and folic acid receptor FRα. This breakthrough discovery will provide accurate templates and design ideas for how to efficiently obtain targeted anti-cancer drugs and other related drugs in the future, and has important academic significance and application value. The research was published online on July 14 in the British journal Nature.
Folic acid receptor is a cell surface receptor that binds and transcribes folic acid and its derivatives. In vivo, it mainly exists in three subtypes: FRα, β and γ. Among them, the expression of FRa in vivo has obvious specific selectivity: low expression in normal cells and high expression in cancer cells. The lack of folic acid in the body is related to many diseases, including cardiovascular disease and cancer.
At the same time, folic acid plays a vital role in the development of normal embryonic neural tube. The proliferation of cancer cells is more dependent on folic acid than normal somatic cells. Folic acid antagonists developed based on this characteristic have been widely used in cancer treatment as the first chemotherapy drugs in the 1940s. However, the clinical use of folic acid antagonists is not selective for FRα, resulting in the death of many non-malignant proliferative cells such as normal bone marrow cells and hair follicles while killing cancer cells Cells (the latter causes hair loss during chemotherapy), leading to serious side effects.
In this research work, the research team obtained the crystal structure of the human FRα and folic acid complex with a diffraction resolution of 2.8Å, and determined the pockets and specific interaction modes of FRα and folic acid. Residues in this pocket involved in folic acid interactions are conserved across all receptor subtypes. The results of this study will provide theoretical guidance and structural basis for the design of novel folic acid antagonists with specific selectivity for FRα at the molecular level. If the research and development is successful, these drugs will specifically inhibit the proliferation of cancer cells overexpressing FRa, thereby greatly reducing the toxic and side effects of traditional folate antagonist chemotherapy.
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