6GTY

Crystal structure of the FimH lectin domain from E.coli K12 in complex with the dimannoside Man(alpha1-6)Man


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.9 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.182 

wwPDB Validation 3D Report Full Report


This is version 1.1 of the entry. See complete history

Literature

Binding of the Bacterial Adhesin FimH to Its Natural, Multivalent High-Mannose Type Glycan Targets.

Sauer, M.M.Jakob, R.P.Luber, T.Canonica, F.Navarra, G.Ernst, B.Unverzagt, C.Maier, T.Glockshuber, R.

(2019) J.Am.Chem.Soc. 141: 936-944

  • DOI: 10.1021/jacs.8b10736
  • Primary Citation of Related Structures:  

  • PubMed Abstract: 
  • Multivalent carbohydrate-lectin interactions at host-pathogen interfaces play a crucial role in the establishment of infections. Although competitive antagonists that prevent pathogen adhesion are promising antimicrobial drugs, the molecular mechanis ...

    Multivalent carbohydrate-lectin interactions at host-pathogen interfaces play a crucial role in the establishment of infections. Although competitive antagonists that prevent pathogen adhesion are promising antimicrobial drugs, the molecular mechanisms underlying these complex adhesion processes are still poorly understood. Here, we characterize the interactions between the fimbrial adhesin FimH from uropathogenic Escherichia coli strains and its natural high-mannose type N-glycan binding epitopes on uroepithelial glycoproteins. Crystal structures and a detailed kinetic characterization of ligand-binding and dissociation revealed that the binding pocket of FimH evolved such that it recognizes the terminal α(1-2)-, α(1-3)-, and α(1-6)-linked mannosides of natural high-mannose type N-glycans with similar affinity. We demonstrate that the 2000-fold higher affinity of the domain-separated state of FimH compared to its domain-associated state is ligand-independent and consistent with a thermodynamic cycle in which ligand-binding shifts the association equilibrium between the FimH lectin and the FimH pilin domain. Moreover, we show that a single N-glycan can bind up to three molecules of FimH, albeit with negative cooperativity, so that a molar excess of accessible N-glycans over FimH on the cell surface favors monovalent FimH binding. Our data provide pivotal insights into the adhesion properties of uropathogenic Escherichia coli strains to their target receptors and a solid basis for the development of effective FimH antagonists.


    Organizational Affiliation

    Institute of Molecular Biology & Biophysics , ETH Zurich , Otto-Stern-Weg 5 , CH-8093 Zurich , Switzerland.,Biozentrum , University of Basel , Klingelbergstrasse 50/70 , CH-4056 Basel , Switzerland.,Department of Pharmaceutical Sciences , University of Basel , Klingelbergstrasse 50 , CH-4056 Basel , Switzerland.,Bioorganische Chemie , University of Bayreuth , D-95440 Bayreuth , Germany.




Macromolecules

Find similar proteins by: Sequence  |  Structure

Entity ID: 1
MoleculeChainsSequence LengthOrganismDetails
Type 1 fimbrin D-mannose specific adhesin
A, B, C, D, E
158Escherichia coli (strain K12)Mutation(s): 0 
Gene Names: fimH
Find proteins for P08191 (Escherichia coli (strain K12))
Go to UniProtKB:  P08191
Small Molecules
Ligands 2 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
MAN
Query on MAN

Download SDF File 
Download CCD File 
A, B, C, D, E
ALPHA-D-MANNOSE
C6 H12 O6
WQZGKKKJIJFFOK-PQMKYFCFSA-N
 Ligand Interaction
MMA
Query on MMA

Download SDF File 
Download CCD File 
A, B, C, D, E
O1-METHYL-MANNOSE
C7 H14 O6
HOVAGTYPODGVJG-VEIUFWFVSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.9 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.182 
  • Space Group: P 43
Unit Cell:
Length (Å)Angle (°)
a = 90.610α = 90.00
b = 90.610β = 90.00
c = 91.530γ = 90.00
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

View Full Validation Report or Ramachandran Plots



Entry History 

Deposition Data

Revision History 

  • Version 1.0: 2019-01-16
    Type: Initial release
  • Version 1.1: 2019-05-01
    Type: Data collection, Database references