1LLR

CHOLERA TOXIN B-PENTAMER WITH LIGAND BMSC-0012

Summary for 1LLR

• Entry DOI: 10.2210/pdb1llr/pdb
• Related: 1EEI 3CHB
• Descriptor: CHOLERA TOXIN B SUBUNIT, 5-aminocarbonyl-3-nitrophenyl alpha-D-galactopyranoside, 3-AMINO-4-{3-[2-(2-PROPOXY-ETHOXY)-ETHOXY]-PROPYLAMINO}-CYCLOBUT-3-ENE-1,2-DIONE, ... (4 entities in total)
• Functional Keywords: enterotoxin, receptor, b-pentamer, toxin
• Biological source: Vibrio cholerae
• Total number of polymer chains: 5
• Total formula weight: 61339.46

Authors

Merritt, E.A.,Hol, W.G.J. (deposition date: 2002-04-30, release date: 2002-08-14, Last modification date: 2024-10-16)

Primary citation

Merritt, E.A.,Zhang, Z.,Pickens, J.C.,Ahn, M.,Hol, W.G.,Fan, E.
Characterization and crystal structure of a high-affinity pentavalent receptor-binding inhibitor for cholera toxin and E. coli heat-labile enterotoxin.
J.Am.Chem.Soc., 124:8818-8824, 2002

PubMed Abstract: Multivalent ligand design constitutes an attractive avenue to the inhibition of receptor recognition and other biological events mediated by oligomeric proteins with multiple binding sites. One example is the design of multivalent receptor blockers targeting members of the AB(5) bacterial toxin family. We report here the synthesis and characterization of a pentavalent inhibitor for cholera toxin and Escherichia coli heat-labile enterotoxin. This inhibitor is an advance over the symmetric pentacyclen-derived inhibitor described in our earlier work in that it presents five copies of m-nitrophenyl-alpha-D-galactoside (MNPG) rather than five copies of beta-D-galactose. The approximately 100-fold higher single-site affinity of MNPG for the toxin receptor binding site relative to galactose is found to yield a proportionate increase in the affinity and IC50 measured for the respective pentavalent constructs. We show by dynamic light scattering that inhibition of receptor binding by the pentavalent inhibitor is due to 1:1 inhibitor:toxin association rather than to inhibitor-mediated aggregation. This 1:1 association is in complete agreement with a 1.46 A resolution crystal structure of the pentavalent inhibitor:toxin complex, which shows that the favorable single-site binding interactions of MNPG are retained by the five arms of the 5256 Da pentavalent MNPG-based inhibitor and that the initial segment of the linking groups interacts with the surface of the toxin B pentamer.

PubMed: 12137534
DOI: 10.1021/ja0202560

Experimental method

X-RAY DIFFRACTION (1.46 Å)