gms | German Medical Science

International Conference on SARS - one year after the (first) outbreak

08. - 11.05.2004, Lübeck

Structural flexibility of SARS coronavirus main proteinase (Mpro)

Poster

  • presenting/speaker Kanchan Anand - Institute of Biochemistry, University of Lübeck, Lübeck, Germany
  • Maojun Yang - Institute of Biochemistry, University of Lübeck, Lübeck, Germany; Laboratory of Structural Biology, Tsinghua University, Beijing, China
  • Na Wang - Institute of Biochemistry, University of Lübeck, Lübeck, Germany
  • Jeroen Mesters - Institute of Biochemistry, University of Lübeck, Lübeck, Germany
  • Mark Bartlam - Laboratory of Structural Biology, Tsinghua University, Beijing, China
  • Zihe Rao - Laboratory of Structural Biology, Tsinghua University, Beijing, China
  • Rolf Hilgenfeld - Institute of Biochemistry, University of Lübeck, Lübeck, Germany

International Conference on SARS - one year after the (first) outbreak. Lübeck, 08.-11.05.2004. Düsseldorf, Köln: German Medical Science; 2004. Doc04sarsP11.03

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/sars2004/04sars131.shtml

Veröffentlicht: 26. Mai 2004

© 2004 Anand et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

The main proteinase (Mpro, also called 3CLpro) is responsible for the majority of cleavages of the SARS coronavirus polyproteins. It is therefore a very attractive target for therapeutic intervention. The first inhibitor suggested to be a useful starting point for the design of anti-SARS drugs, and shown to exhibit antiviral activity in vitro, is in fact directed against the main proteinase [1].

We have determined a number of crystal structures of Mpros from different coronaviruses, including transmissible gastroenteritis virus (TGEV) [2], human coronavirus 229E [1], and SARS coronavirus [3]. These were the first crystal structures of any coronavirus protein. At present, we use crystals of the SARS-CoV Mpro to screen for low-molecular-weight compounds that bind to the enzyme, and could function as potential inhibitors. Naturally, these studies yield a relatively large number of crystal structures of the free enzyme, i.e. with no inhibitor bound. We use this large body of structural information to gain insight into the structural flexibility of the Mpro.

All coronavirus main proteinases analyzed so far form dimers at slightly elevated concentrations in solution and in the crystal. In the case of the SARS-CoV, one of the subunits in the dimer is in a catalytically competent conformation, while the other is not, when the enzyme has been crystallized at pH 6.0 [3]. At higher pH values, however, both monomers are in the active conformation. This earlier observation of ours [3] has been confirmed in the present structures. The pH-dependent conformational transition and its possible biological significance will be discussed. Furthermore, through a detailed comparison of a large number of crystal structures of the SARS-CoV main proteinase, as well as comparisons to the homologous enzymes of TGEV and HCoV 229E, regions of higher flexibility of the protein have been identified. It is found that at least two regions near the substrate-binding site of the proteinase exhibit much-above-average flexibilty. Such data will therefore be useful in rational drug design efforts.


References

1.
K. Anand et al.: Science 300, 1753-1756 (2003)
2.
K. Anand et al.: EMBO J. 21, 2313-2324 (2002)
3.
H. Yang et al.: Proc. Natl. Acad. Sci. USA 100, 13190-13195 (2003)