1tr7: Difference between revisions

Revision as of 16:16, 21 February 2008

FimH adhesin receptor binding domain from uropathogenic E. coli

OverviewOverview

Mannose-binding type 1 pili are important virulence factors for the establishment of Escherichia coli urinary tract infections (UTIs). These infections are initiated by adhesion of uropathogenic E. coli to uroplakin receptors in the uroepithelium via the FimH adhesin located at the tips of type 1 pili. Blocking of bacterial adhesion is able to prevent infection. Here, we provide for the first time binding data of the molecular events underlying type 1 fimbrial adherence, by crystallographic analyses of the FimH receptor binding domains from a uropathogenic and a K-12 strain, and affinity measurements with mannose, common mono- and disaccharides, and a series of alkyl and aryl mannosides. Our results illustrate that the lectin domain of the FimH adhesin is a stable and functional entity and that an exogenous butyl alpha-D-mannoside, bound in the crystal structures, exhibits a significantly better affinity for FimH (Kd = 0.15 microM) than mannose (Kd = 2.3 microM). Exploration of the binding affinities of alpha- d-mannosides with longer alkyl tails revealed affinities up to 5 nM. Aryl mannosides and fructose can also bind with high affinities to the FimH lectin domain, with a 100-fold improvement and 15-fold reduction in affinity, respectively, compared with mannose. Taken together, these relative FimH affinities correlate exceptionally well with the relative concentrations of the same glycans needed for the inhibition of adherence of type 1 piliated E. coli. We foresee that our findings will spark new ideas and initiatives for the development of UTI vaccines and anti-adhesive drugs to prevent anticipated and recurrent UTIs.

About this StructureAbout this Structure

1TR7 is a Single protein structure of sequence from Escherichia coli with , and as ligands. Full crystallographic information is available from OCA.

ReferenceReference

Receptor binding studies disclose a novel class of high-affinity inhibitors of the Escherichia coli FimH adhesin., Bouckaert J, Berglund J, Schembri M, De Genst E, Cools L, Wuhrer M, Hung CS, Pinkner J, Slattegard R, Zavialov A, Choudhury D, Langermann S, Hultgren SJ, Wyns L, Klemm P, Oscarson S, Knight SD, De Greve H, Mol Microbiol. 2005 Jan;55(2):441-55. PMID:15659162

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-[[Image:1tr7.gif|left|200px]]<br /><applet load="1tr7" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1tr7.gif|left|200px]]<br /><applet load="1tr7" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1tr7, resolution 2.10&Aring;" />
 '''FimH adhesin receptor binding domain from uropathogenic E. coli'''<br />
 ==Overview==
-Mannose-binding type 1 pili are important virulence factors for the, establishment of Escherichia coli urinary tract infections (UTIs). These, infections are initiated by adhesion of uropathogenic E. coli to uroplakin, receptors in the uroepithelium via the FimH adhesin located at the tips of, type 1 pili. Blocking of bacterial adhesion is able to prevent infection., Here, we provide for the first time binding data of the molecular events, underlying type 1 fimbrial adherence, by crystallographic analyses of the, FimH receptor binding domains from a uropathogenic and a K-12 strain, and, affinity measurements with mannose, common mono- and disaccharides, and a, series of alkyl and aryl mannosides. Our results illustrate that the, lectin domain of the FimH adhesin is a stable and functional entity and, that an exogenous butyl alpha-D-mannoside, bound in the crystal, structures, exhibits a significantly better affinity for FimH (Kd = 0.15, microM) than mannose (Kd = 2.3 microM). Exploration of the binding, affinities of alpha- d-mannosides with longer alkyl tails revealed, affinities up to 5 nM. Aryl mannosides and fructose can also bind with, high affinities to the FimH lectin domain, with a 100-fold improvement and, 15-fold reduction in affinity, respectively, compared with mannose. Taken, together, these relative FimH affinities correlate exceptionally well with, the relative concentrations of the same glycans needed for the inhibition, of adherence of type 1 piliated E. coli. We foresee that our findings will, spark new ideas and initiatives for the development of UTI vaccines and, anti-adhesive drugs to prevent anticipated and recurrent UTIs.
+Mannose-binding type 1 pili are important virulence factors for the establishment of Escherichia coli urinary tract infections (UTIs). These infections are initiated by adhesion of uropathogenic E. coli to uroplakin receptors in the uroepithelium via the FimH adhesin located at the tips of type 1 pili. Blocking of bacterial adhesion is able to prevent infection. Here, we provide for the first time binding data of the molecular events underlying type 1 fimbrial adherence, by crystallographic analyses of the FimH receptor binding domains from a uropathogenic and a K-12 strain, and affinity measurements with mannose, common mono- and disaccharides, and a series of alkyl and aryl mannosides. Our results illustrate that the lectin domain of the FimH adhesin is a stable and functional entity and that an exogenous butyl alpha-D-mannoside, bound in the crystal structures, exhibits a significantly better affinity for FimH (Kd = 0.15 microM) than mannose (Kd = 2.3 microM). Exploration of the binding affinities of alpha- d-mannosides with longer alkyl tails revealed affinities up to 5 nM. Aryl mannosides and fructose can also bind with high affinities to the FimH lectin domain, with a 100-fold improvement and 15-fold reduction in affinity, respectively, compared with mannose. Taken together, these relative FimH affinities correlate exceptionally well with the relative concentrations of the same glycans needed for the inhibition of adherence of type 1 piliated E. coli. We foresee that our findings will spark new ideas and initiatives for the development of UTI vaccines and anti-adhesive drugs to prevent anticipated and recurrent UTIs.
 ==About this Structure==
-TR7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with CAC, DEG and MPD as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1TR7 OCA].
+TR7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=CAC:'>CAC</scene>, <scene name='pdbligand=DEG:'>DEG</scene> and <scene name='pdbligand=MPD:'>MPD</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TR7 OCA].
 ==Reference==
@@ Line 17: / Line 17: @@
 [[Category: Choudhury, D.]]
 [[Category: Cools, L.]]
-[[Category: Genst, E.De.]]
+[[Category: Genst, E De.]]
-[[Category: Greve, H.De.]]
+[[Category: Greve, H De.]]
-[[Category: Hultgren, S.J.]]
+[[Category: Hultgren, S J.]]
-[[Category: Hung, C.S.]]
+[[Category: Hung, C S.]]
 [[Category: Klemm, P.]]
-[[Category: Knight, S.D.]]
+[[Category: Knight, S D.]]
 [[Category: Langermann, S.]]
 [[Category: Oscarson, S.]]
@@ Line 40: / Line 40: @@
 [[Category: uropathogenic e. coli]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 03:31:45 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:16:30 2008''