Structure of the streptococcal endopeptidase IdeS, a cysteine proteinase with strict specificity for IgG

doi:10.1073/pnas.0407965101

Structure of the streptococcal endopeptidase IdeS, a cysteine proteinase with strict specificity for IgG

^*Department of Structural Research, Max Planck Institute for Biochemistry, D-82152 Martinsried, Germany; ^‡Department of Molecular Biology, Umeå University, SE-90187 Umeå, Sweden; and ^§Department of Cell and Molecular Biology, Biomedical Center, Lund University, B14, SE-221 84 Lund, Sweden

Contributed by Robert Huber, October 28, 2004

Abstract

Pathogenic bacteria have developed complex and diverse virulence mechanisms that weaken or disable the host immune defense system. IdeS (IgG-degrading enzyme of Streptococcus pyogenes) is a secreted cysteine endopeptidase from the human pathogen S. pyogenes with an extraordinarily high degree of substrate specificity, catalyzing a single proteolytic cleavage at the lower hinge of human IgG. This proteolytic degradation promotes inhibition of opsonophagocytosis and interferes with the killing of group A Streptococcus. We have determined the crystal structure of the catalytically inactive mutant IdeS-C94S by x-ray crystallography at 1.9-Å resolution. Despite negligible sequence homology to known proteinases, the core of the structure resembles the canonical papain fold although with major insertions and a distinct substrate-binding site. Therefore IdeS belongs to a unique family within the CA clan of cysteine proteinases. Based on analogy with inhibitor complexes of papain-like proteinases, we propose a model for substrate binding by IdeS.

Footnotes

↵ † To whom correspondence should be addressed. E-mail: wenig{at}biochem.mpg.de.
↵ ¶ Present address: GLYCART Biotechnology AG, CH-8952 Schlieren, Switzerland.
Abbreviations: IdeS, IgG-degrading enzyme of Streptococcus pyogenes; MAD, multiwavelength anomalous diffraction; SeMet, selenomethionine.
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 1Y08).