The Three-dimensional Crystal Structure of Cholera Toxin,☆☆,

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Abstract

The clinical manifestations of cholera are largely attributable to the actions of a secreted hexameric AB5enterotoxin (choleragen). We have independently solved and refined the three-dimensional structure of choleragen at 2.5 Å resolution. The structure of the crystalline toxin closely resembles that described for the heat-labile enterotoxin fromEscherichia coli(LT) with which it shares 80% sequence homology. In both cases, the wedge-shaped A subunit is loosely held high above the plane of the pentameric B subunits by the tethering A2 chain. The most striking difference between the two toxins occurs at the carboxyl terminus of the A2 chain. Whereas the last 14 residues of the A2 chain of LT threading through the central pore of B5assembly form an extended chain with a terminal loop, the A2 chain of choleragen remains a nearly continuous α-helix throughout its length. The four carboxyl-terminal residues of the A2 chain (KDEL sequence), disordered in the crystal structure of LT, are clearly visible in choleragen's electron-density map.

In the accompanying article we describe the three-dimensional structure of the isolated B pentamer of cholera toxin (choleragenoid). Comparison of the crystalline coordinates of choleragen, choleragenoid, and LT provides a solid-three dimensional foundation for further experimental investigation. These structures, along with those of related toxins fromShigella dysenteriaandBordetella pertussis,offer a first step towards the rational design of new vaccines and anti-microbial agents.

Keywords

crystal structure
cholera toxin
choleragenoid
enterotoxins
ADP-ribosylation

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Abbreviations used: CT, cholera toxin (choleragen); CTB, B subunit pentamer of cholera toxin (choleragenoid); LT, heat-labile enterotoxin fromEscherichia coli; ST, shiga toxin; PT, pertussis toxin; VT, verotoxin; GM1Galβ1-3GalNAcβ1-(NeuAcα2-3)4Galβ1-4Glcβ1 ceramide; r.m.s., root-mean-square.

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Present address: D. L. Scott, Medical Services, Massachusetts General Hospital, Boston, MA 02114, USA.

Present address: B. D. Spangler, Department of Biological Sciences and Department of Chemistry, Northern Illinois University, Dekalb, IL 60115, USA.

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