Surprising leads for a cholera toxin receptor-binding antagonist: crystallographic studies of CTB mutants

Structure
E A MerrittW G Hol

Abstract

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. 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...Continue Reading

References

Mar 1, 1991·Acta Crystallographica. Section A, Foundations of Crystallography·T A JonesM Kjeldgaard
Jul 15, 1994·Structure·C L Verlinde, W G Hol
Feb 1, 1994·Protein Science : a Publication of the Protein Society·E A MerrittW G Hol
Nov 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·E A Merritt, M E Murphy

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Citations

Jun 1, 1996·Protein Science : a Publication of the Protein Society·F van den AkkerW G Hol
Jul 1, 1997·Protein Science : a Publication of the Protein Society·E A MerrittW G Hol
Nov 5, 1999·Protein Science : a Publication of the Protein Society·N NaganoJ M Thornton
Jun 6, 2012·Infection and Immunity·Keiji NakamuraShunji Kozaki
Jul 1, 2010·Toxins·Oludare OdumosuWilliam Langridge
Apr 6, 2011·Bioinformation·Gunasagaran ShaminiPandjassarame Kangueane
Jun 28, 2005·Proteins·Alexander BerchanskiMiriam Eisenstein
Sep 13, 2005·Biochimica Et Biophysica Acta·Wayne I Lencer, David Saslowsky
Feb 28, 2018·Journal of Computational Chemistry·Alvaro J Lopez, Leandro Martínez
Feb 13, 2018·PLoS Pathogens·Jakob CervinUlf Yrlid
Nov 4, 2008·Fish Physiology and Biochemistry·Daniel A Fernández, Jorge Calvo
Dec 13, 2006·FEMS Microbiology Letters·Daniel J-F ChinnapenWayne I Lencer
Apr 23, 2008·Current Protocols in Protein Science·Peter D SunJeffrey C Boyington
Jan 1, 2006·EcoSal Plus·Michael G Jobling, Randall K Holmes

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