The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor.
A newly identified severe acute respiratory syndrome coronavirus (SARS-CoV), is the etiological agent responsible for the outbreak of SARS. The SARS-CoV main protease, which is a 33.8-kDa protease (also called the 3C-like protease), plays a pivotal role in mediating viral replication and transcription functions through extensive proteolytic processing of two replicase polyproteins, pp1a (486 kDa) and pp1ab (790 kDa). Here, we report the crystal structures of the SARS-CoV main protease at different pH values and in complex with a specific inhibitor. The protease structure has a fold that can be described as an augmented serine-protease, but with a Cys-His at the active site. This series of crystal structures, which is the first, to our knowledge, of any protein from the SARS virus, reveal substantial pH-dependent conformational changes, and an unexpected mode of inhibitor binding, providing a structural basis for rational drug design.
Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China.
Haitao
H
Yang
Maojun
M
Yang
Yi
Y
Ding
Yiwei
Y
Liu
Zhiyong
Z
Lou
Zhe
Z
Zhou
Lei
L
Sun
Lijuan
L
Mo
Sheng
S
Ye
Hai
H
Pang
George F
GF
Gao
Kanchan
K
Anand
Mark
M
Bartlam
Rolf
R
Hilgenfeld
Zihe
Z
Rao
D000590:Amino Acid Chloromethyl Ketones / Q000737:chemistry; D001665:Binding Sites; D000086782:Coronavirus 3C Proteases; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000737:chemistry*; D005982:Glutathione Transferase / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology*; D013379:Substrate Specificity; D013997:Time Factors; D014764:Viral Proteins / Q000737:chemistry*
D000590:Amino Acid Chloromethyl Ketones; D014764:Viral Proteins; D006639:Histidine; D005982:Glutathione Transferase; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases; D003545:Cysteine