1chq
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SURPRISING LEADS FOR A CHOLERA TOXIN RECEPTOR BINDING ANTAGONIST; CRYSTALLOGRAPHIC STUDIES OF CTB MUTANTS
OverviewOverview
BACKGROUND: Because agents which inhibit the receptor binding of cholera, toxin constitute possible lead compounds for the structure-based design of, anti-cholera drugs, detailed investigation of the toxin's receptor-binding, site is of key importance. The substitution Gly-->Asp at residue 33 of the, cholera toxin B subunit (CTB) has been reported to abolish, receptor-binding ability. The substitution Arg35-->Asp has been reported, to result in deficient assembly of the AB5 holotoxin. The molecular basis, for these effects was not readily apparent from analysis of an earlier, crystal structure of the wild-type toxin B pentamer in a complex with the, receptor pentasaccharide. RESULTS: We now report at a resolution of 2.0 A, the crystal structure of a recombinant CTB pentamer containing the, Gly33-->Asp substitution. The observed conformation of the Asp33 side, chain suggests that the loss in binding affinity is due to a steric clash, with atoms C9 and O9 of the sialic acid moiety of the receptor, ganglioside GM1. The crystal structure also reveals an unexpected mode of, pentamer-pentamer interaction in which pairs of toxin pentamers are joined, by reciprocal insertion of the imidazole ring of His13 from one subunit of, each pentamer into one of the receptor-binding sites on the other. The, surface of interaction at each pentamer-pentamer interface is on the order, of 500 A2, and primarily involves contact of residues 10-14 with the, receptor-binding site on the associated pentamer. This same, pentamer-pentamer interaction is also present in the crystal structure of, a second recombinant CTB containing an Arg-->Asp substitution at residue, 35, which we have determined at 2.1 A resolution. CONCLUSIONS: These, structures suggest that analogs to all or part of the pentapeptide, Ala-Glu-Tyr-His-Asn, corresponding to residues 10-14 of CTB, may, constitute lead compounds for the design of binding-site inhibitors.
About this StructureAbout this Structure
1CHQ is a Single protein structure of sequence from Vibrio cholerae. Full crystallographic information is available from OCA.
ReferenceReference
Surprising leads for a cholera toxin receptor-binding antagonist: crystallographic studies of CTB mutants., Merritt EA, Sarfaty S, Chang TT, Palmer LM, Jobling MG, Holmes RK, Hol WG, Structure. 1995 Jun 15;3(6):561-70. PMID:8590017
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