Blockage of bacterial FimH prevents mucosal inflammation ...
Carbohydrate Recognition by the Fimbrial Adhesion Systems...
Transcript of Carbohydrate Recognition by the Fimbrial Adhesion Systems...
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Lieven ButsVrije Universiteit Brussel
Carbohydrate Recognition by the Fimbrial Adhesion Systems
of Escherichia coli191st Meeting of the Belgian Society
for Biochemistry and Molecular Biology2-Dec-2005
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Protein-Carbohydrate BindingMediates Biological Recognition
● Carbohydrates are highly flexible molecules with a complex stereochemistry and a high density of functional groups; this makes them extremely suitable as information carriers
● The information is encoded by the genome in an indirect way, subject to complex regulation
● Lectins are proteins of non-immune origin that reversibly bind specific carbohydrate structures, without modifying the covalent structure of their ligands
● Biological recognition processes range from microbial infection over intracellular protein trafficking to the differentiation of cells and tissues in higher organisms
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Carbohydrates as Labels
Blood stream
Site ofinfection
Carbohydrates Lectins
Rolling (weak adhesion)
L-selectin ligandsE-selectin ligands E-selectin
L-selectin
Strong adhesion and tissue invasion
Intact, healthy tissue
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Carbohydrates as LiabilitiesInfluenzavirus particle
Respiratory tract epithelium
Haemagglutinin
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Fimbriae or pili bear sugar-binding proteins (adhesins) along their length or at their tips and are involved in the attachment of the bacteria to substrates and host cells; they determine host range and tissue tropism
Bacterial Adhesins
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Adhesion Systems
Chaperone/usherpathway
Nucleation/precipitationpathway
Neisseria meningitidis
Outer membraneadhesins
Moraxella catarrhalis
Adhesins of Gram-positive bacteria
General secretionpathway
Type 1 P-type F17F18 F4/K88 F5/K99
Escherichia coli, Salmonella, ...
Thin aggregative piliCurli
Type IV piliPseudomonas aeruginosaVibrio cholerae
Invasion systemsCS-1 AIDA
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F17 Fimbriae
F17 operon: only 4 genes
Found in enterotoxicogenic Escherichia coli (ETEC) strains infecting livestock
outer membrane
Usher
C
Fimbria(flexible)
G
DChaperone
A
F17-G: adhesin with GlcNAc specificity
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Pilin domain
binding site
C
N
The Adhesin has Two Domains
Complete Ig fold
C
Lectindomain
short linker
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The Adhesin has Two Domains
C
Pilin domain
Lectindomain
short linker
binding site
C
N
Structuralpilin subunit
N-terminalextension
missing strand inincomplete Ig fold
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The Adhesin has Two Domains
C
Pilin domain
Lectindomain
short linker
binding site
C
N
N-terminalextension
missing strand inincomplete Ig fold
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The Adhesin has Two Domains
C
Pilin domain
Lectindomain
short linker
binding site
C
N
N-terminalextension
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The Adhesin has Two Domains
C
Lectindomain
short linker
binding site
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F17 Fimbriae
F17 operon: only 4 genes
Found in enterotoxicogenic Escherichia coli (ETEC) strains infecting livestock
outer membrane
Usher
C
Fimbria(flexible)
G
DChaperone
A
F17-G: adhesin with GlcNAc specificity
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N
C
A Specific ChaperoneAssists Folding and Assembly
N
C
Donor strandcomplementation
Donor strandexchange
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First subunit
Chaperone
G
NTESecondsubunit(truncated)
Zavialov et al., Cell, 113; 587-596.
An X-Ray Snapshot
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A
Outer membrane
Usher
D
Pilus rod(rigid)
AdaptersFG
H FimH adhesin
C Chaperone
A
Type 1 Pili
fim operon
Found in human uropathogenic Escherichia coli (UPEC) strains
FimH adhesin has a basic specificity for mannose
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Therapeutic Strategies
● General antibiotics
● Interfering with pilus assembly
● Interfering with adhesion
● Optimal approach depends on circumstances● Potential for complementarity
● Resistance can arise if used inappropriately● Persistent and recurrent infections can lead to
very long treatment times
● “Pilicides” specifically target chaperone function
● Carbohydrate-based binding site blockers target the adhesin-receptor interaction
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F17G Exhibits SignificantNatural Variation
F17a-G, F17d-G: bovine enterotoxigenic E. coli (ETEC) strains
F17b-G: E. coli strains isolated from septicemic calves and lambs
F17c-G: associated with bovine diarrhea or septicemia and with
lambs showing nephrosis
F17e-G (E. coli strain CK210)
F17f-G (E. coli CK377 strain): expressed by non-enterotoxigenic
E. coli isolated from lambs and goat kids
G fimbriae from human uropathogenic E. coli strains were found
to be identical in amino acid sequence to F17c fimbriae
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Crystal Structure of theF17a-G Lectin Domain
.
OHO
HONHAc
OH
OH
2 -acetamido-2-deoxy-D -glucopyranose
OHO
HONHAc
SeMe
OH
methyl 2-acetamido-2-deoxy-1-seleno- -D-glucopyranoside
(Oscarson lab)
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Crystal Packing Variation
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Sequence Variation
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Crystal Quality Variation
Time to obtain crystals
Maximumresolution
Suitability forsoaking withnew ligands
F17bGF17cG
F17dG
F17eGF17fG
F17aGDays
Minutes
No crystalsobtained N/A N/A
1.1 Å2.1 Å1.8 Å
2.4 Å1.5 Å
+++-
--
-
Days
DaysDays
Prokaryotic genetic diversity is a sourceof complications and opportunities
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Carbohydrate Complexes
GlcNAc(1-3)Gal -methyl-paranitro-phenyl-GlcNAc
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Surface Plasmon ResonanceBinding Experiments
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Surface Plasmon ResonanceBinding Experiments
Glcα1-OMe
Glcβ1-OMe
Time
Response(Resonance
Units)
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F17a-G F17d-GNAG 0.85 ± 0.09 1.00 ± 0.21
1.09 ± 0.04 0.97 ± 0.08
1.02 ± 0.08 1.33 ± 0.11
1.62 ± 0.08 1.92 ± 0.114.58 ± 0.17 4.59 ± 0.562.78 ± 0.10 2.99 ± 0.14
tri 0.64 ± 0.05 0.55 ± 0.08penta 1.19 ± 0.04 1.24 ± 0.05GlcN < 0.1 < 0.1
Not detectable Not detectable< 0.1 < 0.1
Gal Not detectable Not detectableGalNAc Not detectable Not detectable
Ka (1/mM)
NAG2
NAG3
NAG4
β-Me-SeNAGNAGβ1-2Man
α-Me-Glcβ-Me-Glc
Surface Plasmon ResonanceBinding Experiments
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Type 1 Pili
A
Outer membrane
Usher
D
Pilus rod(rigid)
AdapterF
G
H
Tip fibrillum(flexible)
C Chaperone
A
fim operon
Found in human uropathogenic Escherichia coli (UPEC) strains
FimH adhesin has a basic specificity for mannose
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FimH RecognizesTerminal Mannose Residues
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A Serendipitous LigandReveals Remarkable Affinities
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A Competition Assay for Affinity Measurements
Immobilized antibodytargetting the FimH
binding site
Carbohydrate ligands interfere with antibody
binding, preventingthe binding of FimH to
the chip
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-7.62.3 µMmannose
-2.97.6 mMturanose
-2.612.8 mMsucrose
-6.131 µMfructose
-1.4100 mMgalactose
-2.89.24 mMglucose
-4.8300 µMmethyl 2-deoxy-α-D-mannopyranoside
∆G° (kcal/mol)KdLigand
Basic Affinity Pattern
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Fructose, present for about 5% in fruit juices, inhibits type 1 fimbrial adherence
A Naturally Occurring Anti-Adhesive Compound
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Inhibitor DesignAlkyl mannose
derivativesAromatic
substituents
Methylmannose(Man-C1)
Butylmannose(Man-C4)
Octyl-mannose(Man-C8)
Paranitrophenylmannose(PNP-Man)
Methylumbelliferylmannose(MU-Man)
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-10.520MeUmbαMan
-10.044pNPαMan
-10.422octylαman
-11.35heptylαman
-10.910hexylαman
-10.425pentylαman
-9.3151butylαman
-8.9300propylαman
-8.11.2 103ethylαman
-7.72.2 103methylαman
-7.62.3 103mannose
∆G° SPR
(kcal/mol)
Kd SPR (nM)Ligand
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A Linear Correlation Between Alkyl Chain Length and Energy
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Energy
Num
ber
of
con
form
atio
ns
Docking Energy Histograms
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Future Directions
Target tissue Glycoprotein mix
Mixture of fragments
Selection withlectin/adhesin
Binding fragments
Mass spectrometry anddatabase search
Identification
Treatment with proteases and glycosidases
Recovery and digestion
of glycoconjugates
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Structure Thermodynamics
Experiments● BiaCore● ITC, DSC● Spectroscopic● titrations
A + B ABKa
G=-RT.ln(Ka)G=H-T.S
Ka=[AB]eq
[A]eq.[B]eqDocking
Structuredetermination● Crystallography● NMR
Integration
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K88 Fimbriae
outer membraneD
Usher
G
Chaperone
?
E
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Conclusions
OM
UsherChaperone
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Conclusions
● X-ray crystallography reveals the structures of adhesins and their interactions with carobohydrate receptors in atomic detail
● Surface plasmon resonance measurements now enables the detection of the binding of mono- and oligosaccharides, using comparatively small amounts of protein and ligand
● Analysis of the combined data from these techniques provides insights in the specificity profiles of the adhesins, forming the basis for the design of novel adhesion inhibitors
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Acknowledgements
Stefan OscarsonMartina LahmanRikard Slättegård
Ultrastructure Laboratory
Lode WynsRemy LorisJulie BouckaertHenri De GreveErwin De GenstJoris Messens
Stockholm/Goteborg Uppsala
Stefan KnightJenny BerglundAnton ZavialovDeva Choudhury
St. LouisChia HungScott Hultgren
Medimmune Solomon Langermann
Inge Van MolleAdinda Wellens
Fanny CoppensMike SleutelLieve CoolsPeter Bastaerts
Leiden Manfred Wuhrer André Deelder
Kourosch Abbaspour Therani
Organic Synthesis