The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor

doi:10.1073/pnas.1835675100

The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor

^*Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China; and ^‡Institute of Biochemistry, University of Lübeck, 23538 Lübeck, Germany

Communicated by Brian W. Matthews, University of Oregon, Eugene, OR, September 8, 2003 (received for review August 25, 2003)

Abstract

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.

Footnotes

↵ § To whom correspondence should be addressed at: Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China. E-mail: raozh{at}xtal.tsinghua.edu.cn.
↵ † H.Y., M.Y., and Y.D. contributed equally to this work.
Abbreviations: SARS, severe acute respiratory syndrome; CoV, coronavirus; HcoV, human CoV; Mpro, main protease; TGEV, porcine transmissible gastroenteritis virus; PEG, polyethylene glycol; CMK, chloromethyl ketone; N-finger, N-terminal residues 1-7.
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.rcsb.org [PDB ID codes 1UJ1, 1UK3, 1UK2 (SARS-CoV Mpro, apoenzyme at pH 6.0, 7.6, and 8.0, respectively), and 1UK4 (SARS-CoV Mpro in complex with the hexapeptidyl CMK inhibitor].
↵ ¶ World Health Organization press release, August 15, 2003, www.who.int/crs/sars/country/2003_08_15/en.