6YHW

Co-crystals in the P212121 space group, of a beta-cyclodextrin spacered by triazole heptyl from alpha-D-mannose, with FimH lectin at 2.00 A resolution.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.96 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.215 

wwPDB Validation   3D Report Full Report


This is version 2.2 of the entry. See complete history


Literature

The Antiadhesive Strategy in Crohn's Disease: Orally Active Mannosides to Decolonize Pathogenic Escherichia coli from the Gut.

Alvarez Dorta, D.Sivignon, A.Chalopin, T.Dumych, T.I.Roos, G.Bilyy, R.O.Deniaud, D.Krammer, E.M.de Ruyck, J.Lensink, M.F.Bouckaert, J.Barnich, N.Gouin, S.G.

(2016) Chembiochem 17: 936-952

  • DOI: https://doi.org/10.1002/cbic.201600018
  • Primary Citation of Related Structures:  
    6YHW

  • PubMed Abstract: 

    Blocking the adherence of bacteria to cells is an attractive complementary approach to current antibiotic treatments, which are faced with increasing resistance. This strategy has been particularly studied in the context of urinary tract infections (UTIs), in which the adhesion of pathogenic Escherichia coli strains to uroepithelial cells is prevented by blocking the FimH adhesin expressed at the tips of bacteria organelles called fimbriae. Recently, we extended the antiadhesive concept, showing that potent FimH antagonists can block the attachment of adherent-invasive E. coli (AIEC) colonizing the intestinal mucosa of patients with Crohn's disease (CD). In this work, we designed a small library of analogues of heptyl mannoside (HM), a previously identified nanomolar FimH inhibitor, but one that displays poor antiadhesive effects in vivo. The anomeric oxygen atom was replaced by a sulfur or a methylene group to prevent hydrolysis by intestinal glycosidases, and chemical groups were attached at the end of the alkyl tail. Importantly, a lead compound was shown to reduce AIEC levels in the feces and in the colonic and ileal mucosa after oral administration (10 mg kg(-1) ) in a transgenic mouse model of CD. The compound showed a low bioavailability, preferable in this instance, thus suggesting the possibility of setting up an innovative antiadhesive therapy, based on the water-soluble and non-cytotoxic FimH antagonists developed here, for the CD subpopulation in which AIEC plays a key role.


  • Organizational Affiliation

    LUNAM Université, CEISAM, Chimie et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, 2, rue de la Houssinière, BP 92208, 44322, Nantes Cedex 3, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
FimH
A, B
300Escherichia coliMutation(s): 0 
Gene Names: 
UniProt
Find proteins for P08191 (Escherichia coli (strain K12))
Explore P08191 
Go to UniProtKB:  P08191
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08191
Sequence Annotations
Expand
  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
Cycloheptakis-(1-4)-(alpha-D-glucopyranose)
C, D
7N/A
Glycosylation Resources
GlyTouCan:  G01435GL
GlyCosmos:  G01435GL
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.96 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.215 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 63.282α = 90
b = 68.072β = 90
c = 95.777γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2020-05-06
    Type: Initial release
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Author supporting evidence, Data collection, Derived calculations, Non-polymer description, Structure summary
  • Version 2.1: 2021-01-13
    Changes: Database references, Derived calculations, Structure summary
  • Version 2.2: 2024-01-24
    Changes: Data collection, Database references, Refinement description