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J. Biol. Chem., Vol. 281, Issue 35, 25356-25364, September 1, 2006

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Crystal Structure of Staphylococcal Enterotoxin I (SEI) in Complex with a Human Major Histocompatibility Complex Class II Molecule^*

Marisa M. Fernández¹, Rongjin Guan¹², Chittoor P. Swaminathan, Emilio L. Malchiodi, and Roy A. Mariuzza³

From the Cátedra de Inmunología and Instituto de Estudios de la Inmunidad Humoral, Laboratorio de Inmunología Estructural, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 4^to P, 1113 Buenos Aires, Argentina and the Center for Advanced Research in Biotechnology, W. M. Keck Laboratory for Structural Biology, University of Maryland Biotechnology Institute, Rockville, Maryland 20850

Superantigens are bacterial or viral proteins that elicit massive T cell activation through simultaneous binding to major histocompatibility complex (MHC) class II and T cell receptors. This activation results in uncontrolled release of inflammatory cytokines, causing toxic shock. A remarkable property of superantigens, which distinguishes them from T cell receptors, is their ability to interact with multiple MHC class II alleles independently of MHC-bound peptide. Previous crystallographic studies have shown that staphylococcal and streptococcal superantigens belonging to the zinc family bind to a high affinity site on the class II -chain. However, the basis for promiscuous MHC recognition by zinc-dependent superantigens is not obvious, because the -chain is polymorphic and the MHC-bound peptide forms part of the binding interface. To understand how zinc-dependent superantigens recognize MHC, we determined the crystal structure, at 2.0Å resolution, of staphylococcal enterotoxin I bound to the human class II molecule HLA-DR1 bearing a peptide from influenza hemagglutinin. Interactions between the superantigen and DR1 -chain are mediated by a zinc ion, and 22% of the buried surface of peptide·MHC is contributed by the peptide. Comparison of the staphylococcal enterotoxin I·peptide·DR1 structure with ones determined previously revealed that zinc-dependent superantigens achieve promiscuous binding to MHC by targeting conservatively substituted residues of the polymorphic -chain. Additionally, these superantigens circumvent peptide specificity by engaging MHC-bound peptides at their conformationally conserved N-terminal regions while minimizing sequence-specific interactions with peptide residues to enhance cross-reactivity.

Received for publication, April 25, 2006 , and in revised form, June 29, 2006.

^* This work was supported by Agencia Nacional de Promoción Científica y Técnica Grant PICT 12216 (to E. L. M.) and National Institutes of Health Grant AI36900 (to R. A. M.). 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 2G9H) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

¹ These authors contributed equally to this work.

² Current address: Laboratory of Molecular Biology, NIDDK, National Institutes of Health, Bethesda, MD 20892.

³ To whom correspondence should be addressed: Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Inst., 9600 Gudelsky Dr., Rockville, MD 20850. Tel.: 240-314-6243; Fax: 240-314-6255; E-mail: mariuzza{at}carb.nist.gov.

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