Crystal structure of the superantigen staphylococcal enterotoxin type A.

Schad, Elinor; Zaitseva, I. Ya.; Zaĭtsev, V. N.; Dohlsten, Mikael; Kalland, Terje; Schlievert, P M; Ohlendorf, D.H.; Svensson, L.A.

doi:10.1002/j.1460-2075.1995.tb07336.x

Cited by 195 publications

(147 citation statements)

References 38 publications

Supporting

Mentioning

144

Contrasting

Order By: Relevance

“…The structure and function properties of SEA have been well characterized (Abrahmsén et al, 1995;Hudson et al, 1995;Schad et al, 1995). To reduce the systemic toxicity, a major drawback in the use of wild-type SEA (Alphaug et al, 1998), a substitution of Asp 227 has been made.…”

Section: Discussionmentioning

confidence: 99%

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

et al. 2001

View full text Add to dashboard Cite

Summary Superantigens activate T-cells by linking the T-cell receptor to MHC class II on antigen-presenting cells, and novel reactivity can be introduced by fusing the superantigen to a targeting molecule. Thus, an antibody-targeted superantigen, which activates T cells to destroy tumour cells, might be used as cancer therapy. A suitable target is the 5T4 oncofetal antigen, which is expressed on many carcinomas. We constructed a fusion protein from a Fab of a monoclonal antibody recognizing the 5T4 antigen, and an engineered superantigen. The recombinant product 5T4FabV13-SEA D227A bound the 5T4 antigen expressed on the human non-small-cell lung cancer cell line Calu-1 with a K d of 1.2 nM while the substitution of Asp227 to Ala in the superantigen moiety reduced binding activity to MHC class II. 5T4FabV13-SEA D227A tumour reactivity was demonstrated in 7/7 NSCLC samples by immunohistochemistry, while normal tissue reactivity was low to moderate. 5T4FabV13-SEA D227A induced significant T-cell-dependent in vitro killing of sensitive 5T4 bearing Calu-1 cells, with maximum lysis at 10 -10 M, while the capacity to lyse MHC class II expressing cells was approximately 1000 times less effective. Immunotherapy of 5T4FabV13-SEA D227A against human NSCLC was investigated in SCID mice reconstituted with human peripheral blood mononuclear cells. Mice carrying intreperitoneally growing Calu-1 cells showed significant reduction in tumour mass and number after intravenous therapy with 5T4FabV13-SEA D227A . Thus, 5T4FabV13-SEA D227A has highly attractive properties for therapy of human NSCLC.

show abstract

Section: Discussionmentioning

confidence: 99%

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

et al. 2001

View full text Add to dashboard Cite

show abstract

“…Interestingly, zinc was not found in the structure of SEB (16,17), which shares 86% sequence homology with SECs. The zinc ligation in the crystal structures of SEA (18,19), SED (20) 1 The abbreviations used are: SE, staphylococcal enterotoxin; TSS, toxic shock syndrome; SAg, superantigen; TCR, T cell receptor; MHC, major histocompatibility complex; ICP MS, inductively coupled plasma mass spectrometry; SEC, staphylococcal enterotoxin in the type C serogroup. (21), and SEH (22) is found at a different site on the external face of the ␤-sheet wall in the C terminus large domain.…”

mentioning

confidence: 99%

Zinc-mediated Dimerization and Its Effect on Activity and Conformation of Staphylococcal Enterotoxin Type C

Chi¹,

Sadler²,

Jabloński³

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Staphylococcal enterotoxins are superantigen exotoxins that mediate food poisoning and toxic shock syndrome in humans. Despite their structural and functional similarities, superantigens display subtle differences in biological properties and modes of receptor binding as a result of zinc atoms bound differently in their crystal structures. For example, the crystal structures of the staphylococcal enterotoxins in the type C serogroup (SECs) contain a zinc atom coordinated by one aspartate and two histidine residues from one molecule and another aspartate residue from the next molecule, thus forming a dimer. This type of zinc ligation and zinc-mediated dimerization occurs in several SECs, but not in most other staphylococcal enterotoxin serogroups. This prompted us to investigate the potential importance of zinc in SEC-mediated pathogenesis. Site-directed mutagenesis was used to replace SEC zinc binding ligands with alanine. SEC mutants unable to bind zinc did not have major conformational alterations although they failed to form dimers. Zinc binding was not essential for T cell stimulation, emesis, or lethality although in general the mutants were less pyrogenic. Thus the zinc atom in SECs might represent a non-functional heavy atom in an exotoxin group that has diverged from related bacterial toxins containing crucial zinc atoms.

show abstract

“…From these results, the neutralizing epitope of SEA responsible for emetic activity of the toxin may consist in the three peptides regions corresponding to amino acid residues 121-140, 141-160 and 161-180. Based on the three-dimensional structure of SEA molecule [19], these regions are all located on the same domain and the same side of SEA. On the other hand, mutation analysis in SEA and use of different recombinant SEA molecules suggested that residues 47, 61 and 225 are important for emetic activity in monkey [5,7].…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Epitopes on Staphylococcal Enterotoxin A Responsible for Emetic Activity.

Omoe

Saleh

et al. 2001

The Journal of Veterinary Medical Science

View full text Add to dashboard Cite

ABSTRACT. To identify which region of staphylococcal enterotoxin A (SEA) is responsible for the emetic activity, twelve synthetic peptides corresponding to the entire SEA amino acid sequence and their respective anti-peptide antibodies were prepared and tested. The anti-peptide antibodies were tested for neutralization of SEA-induced emesis in Suncus murinus (Shrew mouse). The results indicate that SEA-induced emesis was neutralized by the mixture of three anti-peptide antibodies to A-7 (corresponding to amino acid residues 121-140), A-8 (141-160) and A-9 (160-180). These findings suggest that the regions corresponding to residues 121-180 may be the epitopes responsible for the emetic activity of SEA. KEY WORDS: emetic activity, epitope, staphylococcal enterotoxin, Suncus murinus, synthetic peptide.

show abstract

Crystal structure of the superantigen staphylococcal enterotoxin type A.

Cited by 195 publications

References 38 publications

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

Zinc-mediated Dimerization and Its Effect on Activity and Conformation of Staphylococcal Enterotoxin Type C

Analysis of the Epitopes on Staphylococcal Enterotoxin A Responsible for Emetic Activity.

Contact Info

Product

Resources

About