The three-dimensional fine structure of the new coronavirus RNA polymerase was analyzed

The Shanghai University of Science and Technology-Tsinghua University Joint Anti-New Coronavirus Research Team, composed of Rao Zi and academician/Professor Zhai Zhiyong/Professor Wang Quan, took the lead in successfully analyzing the three-dimensional spatial structure of the RdRp-nsp7-nsp8" complex of the new coronavirus transcription replication machine core unit in the international community, with an overall resolution of 2.9 E (Er).
the study revealed the structural characteristics of the core "engine" of the virus's genetic material transcription replication machine, which laid an important foundation for the development of drugs for new coronary pneumonia. The important results were published April 10 at 10 p.m. in the journal Science.
The day before, the Shanghai University of Science and Technology Institute of Immunochemistry Rao Zi and / Yang Haitao team and partners of the "anti-new coronavirus attack alliance" in Nature jointly published the important research results of the new coronavirus "Structure of Mpro from COVID and 19 virus discovery of its inhibitors", the first international success in the analysis of the new coronavirus key drug target - the main protease (Mpro) high-resolution three-dimensional spatial structure.as of April 10, more than 1.5 million people worldwide had been diagnosed with new crown pneumonia, with unprecedented impact on all mankind.
The pathogen that causes neo-coronary pneumonia is a new type of coronavirus, which has a close affinity with the previously familiar Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and infected patients will be treated with fever, fatigue, dry cough as the main clinical manifestations, severe rapid progression for acute respiratory distress syndrome (SARS-CoV) and even death, so far no special drugs and vaccine approval.
new coronavirus begins to replicate in large numbers after invading host cells, with the process of transcription and replication of the genetic material RNA genome at its core. Transcription of genetic material will eventually be translated to form the structure of the newborn virus to form a protein, and its replication will form the RNA genome of the newborn virus.
RNA polymerase (RdRp), also known as the No. 12 unstructic protein (nsp12), which relies on viral RNA, is able to assemble with several other unstructic proteins to form an efficient RNA synthesis "machine" to complete both processes. RNA polymerase, as the core component of this transcription replication machine, is one of the most important antiviral drug targets, and the destruction of its function is expected to prevent the replication of the virus and ultimately achieve therapeutic purposes.
's high-profile broad-spectrum antiviral drug Favipiravir and Remdesivir or GS-5734, which are still in clinical research, are expected to enter the body and metabolically modify to form final-effect molecules and target viral RNA polymerases.
both are now in clinical trials against the new coronavirus. The research on drug targets of new coronavirus, especially RNA polymerase, is very important for the development of such targeted drugs and the verification of drug ability mechanism.structure analyzed by the study showed that the RNA polymerase of the new coronavirus had conservative characteristics of other viral RNA polymerases and contained niran (Nidovirus RdRp-associated nucleotyltransferase) characteristic domains of the heterovirus, while the viral RNA polymerase and the virus's non-structural proteins nsp7 and nsp8 formed the core unit of the transcription replication machine.
Excitingly, for the first time, researchers have also discovered a unique "β card" domain on the N-side of the RNA polymerase of the new coronavirus, which provides new clues to the biological function of the new coronavirus RNA polymerase.
At the same time, through an in-depth analysis of the atomic resolution structure, the team discovered the key amino acid residues for the functioning of the new coronavirus RNA polymerase, and compared it with the "hepatitis C virus polymerase ns5b-Sofosbuvir effect molecule" complex structure, and proposed that the effect molecules of Redsivir and Fabiravir (i.e., the final product after metabolism) inhibit the possible action of the new coronavirus polymerase.
This study for the first time finely depicts the internal structure of the new coronavirus "RdRp-nsp7-nsp8" transcriptional replication machine, and provides a reasonable mechanism explanation for how the effect molecules of candidate drugs such as Redsivir and Fabiravir accurately target inhibit the synthesis of viral RNA and thus exert its effective activity, which lays an important theoretical foundation for further study of the molecular mechanism of the new coronavirus replication and opens up a new way to develop special effects against new coronary pneumonia.17 March, a preprint of the above results was published online under the title "Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target" (an open preprint repository for biosciences) and the first time information on the results was shared with peers and the public.
in order to facilitate the analysis and use of scientific and technical workers, especially drug developers, the molecular structure coordinate data of the study were also posted to the Protein Structure Database (PDB) and made available to the public under registration numbers 6M71 and 7BTF. At the same time, two structural coordinate data files have also been delivered to the National Microbial Data Center Platform (NMDCS0000002 and NMDCS0000003).
China Science Daily learned from Shanghai University of Science and Technology that the study's genes, prosalytes and other experimental materials will be made available to the public free of charge. At present, the team has issued structural coordinates to dozens of domestic and foreign research institutions and enterprises, including Harvard Medical School, Cambridge University, Fudan University, Chinese Academy of Sciences, Chinese Academy of Medical Sciences, Chinese People's Liberation Army Academy of Military Medicine, etc., and shared the experimental materials with the University of Queensland, the University of Auckland, the University of Cambridge, Columbia University, Stanford University, the University of California, Berkeley and many other domestic and foreign institutions.
it is also understood that since this year, the University has published four major scientific research achievements in the world's top academic journals.
in addition to the two above issued on Science and Nature, the latest research results of the iHuman Institute Executive Director Liu Zhijie's research team on the structure and function of human-sourced cannabinin are published online in Cell on January 31.
February 20, the Xu Fei Task Force of the iHuman Institute and the Cooperative Group analyzed the results of the first three-dimensional structure of orphaned subjects and published them online on Nature. (Source: Huang Xin, China Science Journal)
relevant paper information: