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

Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13190-5. doi: 10.1073/pnas.1835675100. Epub 2003 Oct 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / chemistry
  • Binding Sites
  • Coronavirus 3C Proteases
  • Crystallography, X-Ray
  • Cysteine / chemistry
  • Cysteine Endopeptidases
  • Endopeptidases / chemistry*
  • Glutathione Transferase / chemistry
  • Histidine / chemistry
  • Hydrogen-Ion Concentration
  • Models, Chemical
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • SARS Virus / enzymology*
  • Substrate Specificity
  • Time Factors
  • Viral Proteins / chemistry*

Substances

  • Amino Acid Chloromethyl Ketones
  • Viral Proteins
  • Histidine
  • Glutathione Transferase
  • Endopeptidases
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases
  • Cysteine

Associated data

  • PDB/1UJ1
  • PDB/1UK2
  • PDB/1UK3
  • PDB/1UK4