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J. Biol. Chem., Vol. 283, Issue 46, 31279-31283, November 14, 2008

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The Structural Basis for T-antigen Hydrolysis by Streptococcus pneumoniae

A TARGET FOR STRUCTURE-BASED VACCINE DESIGN^*

Matthew E. C. Caines, Haizhong Zhu, Marija Vuckovic, Lisa M. Willis^¶, Stephen G. Withers^||, Warren W. Wakarchuk^¶, and Natalie C. J. Strynadka¹

From the Department of Biochemistry and Molecular Biology, Centre for Blood Research and ^||Department of Chemistry, University of British Columbia, Vancouver, British Columbia, V6T 1Z3 and the ^¶National Research Council of Canada, Institute for Biological Sciences, Ottawa, Ontario, K1A 0R6, Canada

Streptococcus pneumoniae endo--N-acetylgalactosaminidase is a cell surface-anchored glycoside hydrolase from family GH101 involved in the breakdown of mucin type O-linked glycans. The 189-kDa mature enzyme specifically hydrolyzes the T-antigen disaccharide from extracellular host glycoproteins and is representative of a broadly important class of virulence factors that have remained structurally uncharacterized due to their large size and highly modular nature. Here we report a 2.9 Å resolution crystal structure that remarkably captures the multidomain architecture and characterizes a catalytic center unexpectedly resembling that of -amylases. Our analysis presents a complete model of glycoprotein recognition and provides a basis for the structure-based design of novel Streptococcus vaccines and therapeutics.

Received for publication, July 25, 2008 , and in revised form, September 4, 2008.

^* This work was funded by the Howard Hughes Medical Institute, Canadian Institutes of Health Research, Michael Smith Foundation for Health Research, and Canada Foundation for Innovation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (code 3ECQ) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The on-line version of this article (available at http://www.jbc.org) contains supplemental text, three supplemental figures, and a supplemental movie.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, Canada. Tel.: 604-822-0789; Fax: 604-822-5227; E-mail: natalie{at}byron.biochem.ubc.ca.

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