1PZK

Cholera Toxin B-Pentamer Complexed With N-Acyl Phenyl Galactoside 9h

Summary for 1PZK

• Entry DOI: 10.2210/pdb1pzk/pdb
• Related: 1PZI 1PZJ
• Descriptor: Cholera Toxin B Subunit, N-{3-[4-(3-AMINO-PROPYL)-PIPERAZIN-1-YL]-PROPYL}-3-(2-THIOPHEN-2-YL-ACETYLAMINO)-5-(3,4,5-TRIHYDROXY-6-HYDROXYMETHYL-TETRAHYDRO-PYRAN-2-YLOXY)-BENZAMIDE (3 entities in total)
• Functional Keywords: pentamer, monovalent, toxin, inhibitor, cholera
• Biological source: Vibrio cholerae
• Total number of polymer chains: 5
• Total formula weight: 61225.06

Authors

Mitchell, D.D.,Pickens, J.C.,Korotkov, K.,Fan, E.,Hol, W.G.J. (deposition date: 2003-07-11, release date: 2004-03-09, Last modification date: 2023-08-16)

Primary citation

Mitchell, D.D.,Pickens, J.C.,Korotkov, K.,Fan, E.,Hol, W.G.J.
3,5-Substituted phenyl galactosides as leads in designing effective cholera toxin antagonists; synthesis and crystallographic studies
Bioorg.Med.Chem., 12:907-920, 2004

PubMed Abstract: With the aim of developing high-affinity mono and multivalent antagonists of cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT) we are using the galactose portion of the natural receptor ganglioside GM1 as an anchoring fragment in structure-based inhibitor design efforts. In order to establish a better structure-activity relationship for guiding these studies, we designed and prepared a small focused library of twenty 3,5-substituted phenylgalactosides based on two previous leads. The compounds were tested for their ability to block CTB(5) binding to immobilized ganglioside receptor and compared to the two previous leads. The crystal structures of the most promising compounds bound to either CTB(5) or LTB(5) were then determined in order to understand the basis for affinity differences. The most potent new compound yielded a six-fold improvement over our benchmark lead m-nitrophenyl-alpha-d-galactopyranoside (MNPG), and a two-fold improvement in IC(50) over a newer MNPG derivative. These results support the notion that the m-nitrophenyl moiety of MNPG and its derivatives is an important element to retain in future optimization efforts. Additionally, a consensus binding-pocket for the alkylmorpholine or piperazine moiety present in all of the designed antagonists was established as an important area of the GM1 binding site to target in future work.

PubMed: 14980603
DOI: 10.1016/j.bmc.2003.12.019

Experimental method

X-RAY DIFFRACTION (1.35 Å)