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| | {{STRUCTURE_1chp| PDB=1chp | SCENE= }} | | {{STRUCTURE_1chp| PDB=1chp | SCENE= }} |
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| - | '''SURPRISING LEADS FOR A CHOLERA TOXIN RECEPTOR BINDING ANTAGONIST; CRYSTALLOGRAPHIC STUDIES OF CTB MUTANTS'''
| + | ===SURPRISING LEADS FOR A CHOLERA TOXIN RECEPTOR BINDING ANTAGONIST; CRYSTALLOGRAPHIC STUDIES OF CTB MUTANTS=== |
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| - | ==Overview==
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| - | 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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_8590017}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 8590017 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_8590017}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Merritt, E A.]] | | [[Category: Merritt, E A.]] |
| | [[Category: Toxin]] | | [[Category: Toxin]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 12:44:30 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 20:45:37 2008'' |
Revision as of 17:45, 30 June 2008
Template:STRUCTURE 1chp
SURPRISING LEADS FOR A CHOLERA TOXIN RECEPTOR BINDING ANTAGONIST; CRYSTALLOGRAPHIC STUDIES OF CTB MUTANTS
Template:ABSTRACT PUBMED 8590017
About this Structure
1CHP is a Single protein structure of sequence from Vibrio cholerae. Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Mon Jun 30 20:45:37 2008
