From 2002 to 2003, a SARS epidemic that broke out in China and quickly spread across the world has left a deep memory for many people. After ten years, a new outbreak of respiratory syndrome broke out in the Middle East in 2012. As of March 2017, it has affected 27 countries and regions around the world with a mortality rate of 35%, which seriously threatens world public health security. In 2015, the Middle East Respiratory Syndrome broke out locally in South Korea, which sounded the alarm for epidemic prevention and control.
The culprits of SARS, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) are members of the coronavirus. This type of virus is named after its corona-like periphery visible under an electron microscope. Coronavirus is a single-stranded positive-stranded RNA virus with an envelope that belongs to the Coronaviridae family. Coronavirus infections are associated with many diseases in humans and animals, and have an addictive nature to the gastrointestinal tract, respiratory tract, and nervous system.
In order to more effectively deal with the serious threats to public health caused by SARS-CoV and MERS-CoV, scientists urgently need to understand their pathogenic mechanisms. Confirming which host cell molecule the virus recognizes as a receptor, and how the virus adheres to the receptor to invade the host cell to initiate infection are key links in the study of pathogenic mechanisms.
Spike protein (S) is responsible for virus receptor binding and membrane fusion, and is the main target of vaccines and drugs. The coronavirus S protein is cut into two subunits, S1 and S2. S1 is responsible for receptor recognition and S2 is responsible for membrane fusion. S1 can be divided into N-terminal domain (NTD) and C-terminal domain (CTD). The C-terminal domain has been confirmed as the binding region of the MERS-CoV receptor CD26, so it is also called the RBD region (Recepter Binding Domain). The S proteins of MERS-CoV, SARS-CoV, and other coronaviruses are of great significance for cross-species transmission of the virus. Among them, spike proteinase have critical role on the characteristics of spike proteins, the binding characteristics with host receptor molecules, and the digestion of spike proteins.
The crystal structure of the high-resolution complex of CoV RBD and human receptor CD26 reveals the molecular mechanism of virus-receptor binding. Subsequently, the structure of the core region of S2 was analyzed, and the membrane fusion mechanism of virus and receptor cells was revealed. At the same time, peptide inhibitors based on S2 can also inhibit virus invasion, providing a structural basis for future drug and inhibitor design. Researches on MERS-CoV humanized antibodies is of great significance for the treatment of MERS-CoV. In addition, studies on MERS-CoV closely related coronaviruses, such as HKU4, etc., have revealed a cross-species transmission pathway for MERS-CoV. To fully understand the MERS-CoV S and SARS-CoV S proteins, it is also necessary to understand the three-dimensional spatial arrangement of NTD and RBD and the interaction mode of S1 and S2 subunits, but it is limited by the unknown structure of the S protein. The overall knowledge of the S protein is still very limited.
According to the structural analysis, the unique sugar-binding region of MERS-CoV and SARS-CoV spike proteins NTD determines that they cannot complete the virus adhesion to cells by binding sugar molecules like some coronavirus NTDs. The NTD and RBD of the S protein are structurally adjacent, and the NTD also has the potential to act as a target for neutralizing antibodies. Conservative analysis of six coronavirus sequences in infected humans found that the fusion peptide, heptapeptide repeat region 1 (HR1), and central helix are relatively conserved and accessible regions, and are looking to develop broad-spectrum neutralizing antibodies and inhibitors Ideal site for agents.
The full-length S protein trimer structure analysis of coronavirus MERS-CoV, SARS-CoV has important theoretical significance for understanding the pathogenicity mechanism and cross-species transmission mechanism of MERS-CoV and SARS-CoV, and is useful for targeting the virus invasion process and the practice of specific drug development and vaccine design.