Subjects: Biology >> Virology submitted time 2020-03-06
Abstract： Global emergencies caused by the zoonotic severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and the newly discovered 2019 novel coronavirus (2019-nCoV) have posed a serious threat to human health. The spike (S) glycoprotein, a homotrimer located on the surface of the viral envelope, is the key antigen for therapeutic development. The S2 subunit from the S glycoprotein, which is highly conserved among coronaviruses, contributes to viral entry by mediating the host-viral membrane fusion. However, the structural information of the post-fusion S2 machinery from these highly pathogenic human-infecting coronaviruses is still lacking. Here, we report the structure of SARS-CoV S glycoprotein in the post-fusion state by single particle cryo-electron microscopy, revealing a more rotated HR1-HR2 six-helix bundle and a tightly bound linker region upstream of the HR2 motif that plays an important role in membrane fusion. Comparison with the structure of pre-fusion SARS-CoV S glycoprotein shows dramatic structural rearrangements and conformational changes, resembling that of the Mouse hepatitis virus (MHV) and other class I viral fusion proteins. By analyzing the structural features, describing the glycan shield and mapping the antibody and inhibitor targets on the surface of the post-fusion S glycoprotein, we provide structural basis of potential therapeutic targets within the highly conserved S2 subunit, which may help the development of effective vaccines and therapies against a wide range of SARS-like coronaviruses. " "
Peer Review Status:
Awaiting Review
Subjects: Biology >> Biophysics >> Cell Biology submitted time 2016-05-12
Cao, Duanfang
Wang, Mingzhu
Yang, Na
Xu, Rui-Ming
Cao, Duanfang
Xu, Rui-Ming
Qiu, Xiayang
Liu, Dongxiang
Jiang, Hualiang
Abstract： Sirtuins with an extended N-terminal domain (NTD), represented by yeast Sir2 and human SIRT1, harbor intrinsic mechanisms for regulation of their NAD-dependent deacetylase activities. Elucidation of the regulatory mechanisms is crucial for understanding the biological functions of sirtuins and development of potential therapeutics. In particular, SIRT1 has emerged as an attractive therapeutic target, and the search for SIRT1-activating compounds (STACs) has been actively pursued. However, the effectiveness of a class of reported STACs (represented by resveratrol) as direct SIRT1 activators is under debate due to the complication involving the use of fluorogenic substrates in in vitro assays. Future efforts of SIRT1-based therapeutics necessitate the dissection of the molecular mechanism of SIRT1 stimulation. We solved the structure of SIRT1 in complex with resveratrol and a 7-amino-4-methylcoumarin (AMC)-containing peptide. The structure reveals the presence of three resveratrol molecules, two of which mediate the interaction between the AMC peptide and the NTD of SIRT1. The two NTD-bound resveratrol molecules are principally responsible for promoting tighter binding between SIRT1 and the peptide and the stimulation of SIRT1 activity. The structural information provides valuable insights into regulation of SIRT1 activity and should benefit the development of authentic SIRT1 activators.
Peer Review Status:Awaiting Review
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