4AVH

Structure of the FimH lectin domain in the trigonal space group, in complex with a thioalkyl alpha-D-mannoside at 2.1 A resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 

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This is version 1.3 of the entry. See complete history


Literature

The Tyrosine Gate as a Potential Entropic Lever in the Receptor-Binding Site of the Bacterial Adhesin Fimh.

Wellens, A.Lahmann, M.Touaibia, M.Vaucher, J.Oscarson, S.Roy, R.Remaut, H.Bouckaert, J.

(2012) Biochemistry 51: 4790

  • DOI: https://doi.org/10.1021/bi300251r
  • Primary Citation of Related Structures:  
    4AUU, 4AUY, 4AV0, 4AV4, 4AV5, 4AVH, 4AVI, 4AVJ, 4AVK

  • PubMed Abstract: 

    Uropathogenic Escherichia coli (UPEC) are the major causative agents of urinary tract infections. During infection, UPEC adhere to mannosylated glycoreceptors on the urothelium via the FimH adhesin located at the tip of type 1 pili. Synthetic FimH antiadhesives such as alkyl and phenyl α-D-mannopyranosides are thus ideal candidates for the chemical interception of this crucial step in pathogenesis. The crystal structures of the FimH lectin domain in its ligand-free form and in complexes with eight medium- and high-affinity mannopyranoside inhibitors are presented. The thermodynamic profiles of the FimH-inhibitor interactions indicate that the binding of FimH to α-D-mannopyranose is enthalpy-driven and has a negative entropic change. Addition of a hydrophobic aglycon influences the binding enthalpy and can induce a favorable entropic change. The alleviation of the entropic cost is at least in part explained by increased dynamics in the tyrosine gate (Tyr48 and Tyr137) of the FimH receptor-binding site upon binding of the ligand. Ligands with a phenyl group directly linked to the anomeric oxygen of α-D-mannose introduce the largest dynamics into the Tyr48 side chain, because conjugation with the anomeric oxygen of α-D-mannose forces the aromatic aglycon into a conformation that comes into close contact (≈2.65 Å) with Tyr48. A propargyl group in this position predetermines the orientation of the aglycon and significantly decreases affinity. FimH has the highest affinity for α-D-mannopyranosides substituted with hydrophobic aglycons that are compatible in shape and electrostatic properties to the tyrosine gate, such as heptyl α-D-mannose.


  • Organizational Affiliation

    Structural Molecular Microbiology, Vrije Universiteit Brussel, VIB, Brussels, Belgium.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
FIMH
A, B
158Escherichia coli UTI89Mutation(s): 0 
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
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
FK9 Binding MOAD:  4AVH Kd: 59.5 (nM) from 1 assay(s)
PDBBind:  4AVH Kd: 59.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.31α = 90
b = 91.31β = 90
c = 80.3γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata 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: 2012-06-27
    Type: Initial release
  • Version 1.1: 2012-09-05
    Changes: Database references
  • Version 1.2: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Derived calculations, Other, Structure summary
  • Version 1.3: 2023-12-20
    Changes: Data collection, Database references, Refinement description, Structure summary