ABSTRACT
I. INTRODUCTION 186 A. The Two Toxins 186 B. Membrane Binding 186 C. Enzymatic Activity 189
II. X-RAY DIFFRACTION STUDIES 192 A. The B Subunit and the B Pentamer 193 B. The A Subunit 195 C. Architecture of the ABs Holotoxin 197 D. Flexibility of the A Subunit with Respect to the B Pentamer 199 E. Interactions of Divalent Cations with L T 200 F. The Active Site of L T 201 G. Receptor Recognition by L T and CT 204
Ill. ORIENTATION OF ABs BOUND TO THE MEMBRANE 210 A. Noncrystallographic Investigations 210 B. Crystallographic Results 211 C. The C-Terminal [K/R]DEL Sequence of the A Subunit 211
IV. THERAPEUTIC APPLICATIONS 212 A. LT, CT, and Vaccine Development 212 B. Adjuvant Activity of LT and CT 213 c. Prospects for Drug Design 213
REFERENCES 215
186 Hoi eta/.
In 1959 it was recognized for the first time that the major virulence factor of the cholera-causing bacteria Vibrio cholerae 01 is a secreted protein, thereafter called cholera toxin (CT) (De, 1959; Dutta et al., 1959). At that time De had already discovered that certain coliform bacteria also can cause a cholera-like disease (De et al., 1956). In the late 1960s it was found that enterotoxigenic Escherichia coli (ETEC) produces a toxin (Smith and Halls, 1967) that is immunologically related to cholera toxin (Gyles and Barnum, 1969) and has similar effects (Gorbach et al., 1971). This protein was called heat-labile enterotoxin (LT) and constitutes the major subject of this chapter.
