1PZI

Heat-Labile Enterotoxin B-Pentamer Complexed With Nitrophenyl Galactoside 2a


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.158 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

3,5-Substituted phenyl galactosides as leads in designing effective cholera toxin antagonists; synthesis and crystallographic studies

Mitchell, D.D.Pickens, J.C.Korotkov, K.Fan, E.Hol, W.G.J.

(2004) Bioorg Med Chem 12: 907-920

  • DOI: https://doi.org/10.1016/j.bmc.2003.12.019
  • Primary Citation of Related Structures:  
    1PZI, 1PZJ, 1PZK

  • 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.


  • Organizational Affiliation

    Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Heat-labile Enterotoxin B subunitA [auth D],
B [auth E],
C [auth F],
D [auth G],
E [auth H]
103Escherichia coliMutation(s): 0 
Gene Names: ELTB
UniProt
Find proteins for P32890 (Escherichia coli)
Explore P32890 
Go to UniProtKB:  P32890
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP32890
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
1DM PDBBind:  1PZI Kd: 6.00e+4 (nM) from 1 assay(s)
Binding MOAD:  1PZI Kd: 6.00e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.158 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 60.817α = 90
b = 78.683β = 116.2
c = 62.3γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
TRUNCATEdata reduction
XTALVIEWrefinement
HKL-2000data collection
HKL-2000data reduction
CCP4data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-03-09
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2019-07-24
    Changes: Data collection, Refinement description
  • Version 1.4: 2023-08-16
    Changes: Data collection, Database references, Derived calculations, Refinement description