Molecular Mechanism Of SARS-CoV Spike Glycoprotein Mediate Viral And Cellular Membrane Fusion

MERS-CoV and SARS-CoV are two newly emerging highly pathogenic coronaviruses in the 21 st century.There are still many unresolved scientific questions regarding to the basic research and development of clinical medicine and vaccines against these two viruses.The envelope spike glycoprotein(S protein)of coronavirus binds to the host cellular receptor,and mediates the membrane fusion,and plays critical roles in viral cell entry,and is also the important target of host neutralizing antibody response and drug development.The S protein on the virion surface belongs to the class I viral fusion protein,mediate the fusion of viral and cellular membranes through a pre-to post fusion conformational transition.However,the structural and mechanism undering the S protein conformational changes during the viral entry remains unknown.In the present study,we solve the different conformations of the spike before,during and after the membrane fusion by cryo-EM method,elucidating how the conformational changes mediate the membrane fusion during viral cell entry.The cryo-EM structure of SARS-CoV S protein in pre-fusion state shows that there are four conformations exist.One is receptor binding inactive state with three CTD1 s in “down” conformation,and three are receptor binding active state,with one of the “CTD1s” tilts up to a different degree.And the receptor binding S complex verifies the result.Besides the pre-fusion state and the receptor binding state,we also capture the states of intermediate and postfusion states by mimic the viral entry enviroment.In conclusion,we report the prerequisite conformational state for SARS-CoV S protein for receptor binding,and capture the intermediate-and post-fusion state of SARSCoV S protein.These results can be extended to other coronavirus using CTD1 as the receptor binding domain,such as MERS,which provide a better understanding of the cell entry of highly pathogenic coronaviruses.