Scientists analyze the three-dimensional structure of "drug target-drug"

the early hours of April 24, Beijing time, Science published a research paper online in the form of Research Article by Rao Zi of the Institute of Immunochemistry of Shanghai University of Science and Technology and a research team of academicians and partners. It is reported that this work successfully analyzed the "drug target-drug" three-dimensional structure of EmbA-EmbB and EmbC-EmbC, the key Arab glycosyl transferase complex of Mycobacteria for the first time in the world, and for the first time revealed the precise molecular mechanism of the first-line anti-tuberculosis drug ethylamine butanol acting on the target, laying an important foundation for the development of new anti-tuberculosis drugs to solve the problem of tuberculosis resistance.
is one of the world's top 10 deadly diseases and the "number one killer" of a single infectious disease (ranked above AIDS and malaria). At present, the first-line drugs to treat tuberculosis were developed in the 1940s and 1960s and have been used for more than half a century. The problem of drug resistance has arisen and become more serious, even without medical treatment, which has brought unprecedented pressure to tuberculosis prevention and public health security. Therefore, the research on the target of anti-tuberculosis drugs and the development of new drugs are urgent.
Mycobacterium tuberculosis is a pathogen causing tuberculosis, its cell walls are very special, the main components include mycobacteric acid (MA), Arabic semi-lactose (AG), peptide polysaccharides (PG) and lipid Arab polysaccharides (LAM), etc., which play a natural protective role for TB bacteria. Inhibiting the synthesis of cell wall components is considered a reasonable idea for the development of new anti-tuberculosis drugs. Currently used first-line anti-TB drugs isoniazid, ethylamine butanol, etc. are by inhibiting cell wall synthesis to play a role. Studies have shown that ethyl butanol targets the Arabic glycosyl transfer enzymes EmbA, EmbB and EmbC involved in AG and LAM synthesis. However, since the advent of the drug, its molecular mechanism has not been unexplored, it is not possible to replace the "traditional old drug" ethylamine butanol to solve its growing drug resistance problem.
of EmbA and EmbB show that EmbA and EmbB play physiological functions in the form of heterogeneity. In a surprising discovery, the AcpM protein involved in cell wall MA synthesis binds to the inner cells of each Emb protein, forming the EmbA-EmbB-AcpM2 and EmbC2-AcpM2 complexes, respectively. Each Emb protein structure can be divided into one 15-times trans-membrane domain and two extracellation domains containing jelly-roll folding forms, while the active pockets are located between the trans-membrane domain and the extracellulation domain. The study analyzed the precise binding methods of Arabic sugar supply (DPA) and second sugar (Ara2) at the active site.
further studies have found that ethyl butanol is also combined with the active pockets of EmbB and EmbC, and that its binding site occupies the substrate binding position (D-site and A0-site) on both sides of the catalytic amino acid Asp, which simultaneously blocks the binding of Arabic sugar feeders and receptors, ultimately inhibiting the synthesis of cell wall AG and LAM. By analyzing the clinically drug-resistant mutation site of ethyl butanol, the team found that most of the site was near the drug binding locations of EmbB and EmbC. Mutations in the associated bit amino acids can directly or indirectly affect the binding of ethyl butanol. Therefore, in order to solve the problem of drug resistance, it is necessary to consider avoiding the spatial effects of these places when designing new drugs. The above research results will lay a solid structural theoretical foundation for the optimization of ethyl butanol and the development of new drugs targeting Emb protein.
the completion of this work marks rao and the team's years of efforts to basically conquer the only known strategic highlands in the key TB drug target areas. At present, the research team is making full use of the advantages of Shanghai University of Science and Technology and Zhangjiang Biopharmaceutical Industry Base, through comprehensive cooperation, to promote the research and development of new anti-tuberculosis drugs, accelerate the transformation of basic research results. (Source: Huang Xin, China Science Journal)
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