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| | <StructureSection load='5f2f' size='340' side='right'caption='[[5f2f]], [[Resolution|resolution]] 1.67Å' scene=''> | | <StructureSection load='5f2f' size='340' side='right'caption='[[5f2f]], [[Resolution|resolution]] 1.67Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5f2f]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Escherichia_coli_j96 Escherichia coli j96]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5F2F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5F2F FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5f2f]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_J96 Escherichia coli J96]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5F2F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5F2F FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5U7:5-[4-[(2~{R},3~{S},4~{S},5~{S},6~{R})-6-(HYDROXYMETHYL)-3,4,5-TRIS(OXIDANYL)OXAN-2-YL]OXY-3-METHYL-PHENYL]-~{N}1,~{N}3-DIMETHYL-BENZENE-1,3-DICARBOXAMIDE'>5U7</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.665Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">fimH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1206108 Escherichia coli J96])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5U7:5-[4-[(2~{R},3~{S},4~{S},5~{S},6~{R})-6-(HYDROXYMETHYL)-3,4,5-TRIS(OXIDANYL)OXAN-2-YL]OXY-3-METHYL-PHENYL]-~{N}1,~{N}3-DIMETHYL-BENZENE-1,3-DICARBOXAMIDE'>5U7</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5f2f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5f2f OCA], [http://pdbe.org/5f2f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5f2f RCSB], [http://www.ebi.ac.uk/pdbsum/5f2f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5f2f ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5f2f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5f2f OCA], [https://pdbe.org/5f2f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5f2f RCSB], [https://www.ebi.ac.uk/pdbsum/5f2f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5f2f ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FIMH_ECOLI FIMH_ECOLI]] Involved in regulation of length and mediation of adhesion of type 1 fimbriae (but not necessary for the production of fimbriae). Adhesin responsible for the binding to D-mannose. It is laterally positioned at intervals in the structure of the type 1 fimbriae. In order to integrate FimH in the fimbriae FimF and FimG are needed. | + | [https://www.uniprot.org/uniprot/FIMH_ECOLI FIMH_ECOLI] Involved in regulation of length and mediation of adhesion of type 1 fimbriae (but not necessary for the production of fimbriae). Adhesin responsible for the binding to D-mannose. It is laterally positioned at intervals in the structure of the type 1 fimbriae. In order to integrate FimH in the fimbriae FimF and FimG are needed. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Escherichia coli j96]] | + | [[Category: Escherichia coli J96]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Hultgren, S J]] | + | [[Category: Hultgren SJ]] |
| - | [[Category: Kalas, V]] | + | [[Category: Kalas V]] |
| - | [[Category: Carbohydrate binding protein]]
| + | |
| - | [[Category: Immunoglobulin fold]]
| + | |
| - | [[Category: Lectin]]
| + | |
| - | [[Category: Mannoside]]
| + | |
| - | [[Category: Sugar binding protein]]
| + | |
| Structural highlights
Function
FIMH_ECOLI Involved in regulation of length and mediation of adhesion of type 1 fimbriae (but not necessary for the production of fimbriae). Adhesin responsible for the binding to D-mannose. It is laterally positioned at intervals in the structure of the type 1 fimbriae. In order to integrate FimH in the fimbriae FimF and FimG are needed.
Publication Abstract from PubMed
Uropathogenic E. coli (UPEC) employ the mannose-binding adhesin FimH to colonize the bladder epithelium during urinary tract infection (UTI). Previously reported FimH antagonists exhibit good potency and efficacy, but low bioavailability and a short half-life in vivo. In a rational design strategy, we obtained an X-ray structure of lead mannosides and then designed mannosides with improved drug-like properties. We show that cyclizing the carboxamide onto the biphenyl B-ring aglycone of biphenyl mannosides into a fused heterocyclic ring, generates new biaryl mannosides such as isoquinolone 22 (2-methyl-4-(1-oxo-1,2-dihydroisoquinolin-7-yl)phenyl alpha-d-mannopyranoside) with enhanced potency and in vivo efficacy resulting from increased oral bioavailability. N-Substitution of the isoquinolone aglycone with various functionalities produced a new potent subseries of FimH antagonists. All analogues of the subseries have higher FimH binding affinity than unsubstituted lead 22, as determined by thermal shift differential scanning fluorimetry assay. Mannosides with pyridyl substitution on the isoquinolone group inhibit bacteria-mediated hemagglutination and prevent biofilm formation by UPEC with single-digit nanomolar potency, which is unprecedented for any FimH antagonists or any other antivirulence compounds reported to date.
Antivirulence Isoquinolone Mannosides: Optimization of the Biaryl Aglycone for FimH Lectin Binding Affinity and Efficacy in the Treatment of Chronic UTI.,Jarvis C, Han Z, Kalas V, Klein R, Pinkner JS, Ford B, Binkley J, Cusumano CK, Cusumano Z, Mydock-McGrane L, Hultgren SJ, Janetka JW ChemMedChem. 2016 Feb;11(4):367-73. doi: 10.1002/cmdc.201600006. Epub 2016 Jan, 26. PMID:26812660[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Jarvis C, Han Z, Kalas V, Klein R, Pinkner JS, Ford B, Binkley J, Cusumano CK, Cusumano Z, Mydock-McGrane L, Hultgren SJ, Janetka JW. Antivirulence Isoquinolone Mannosides: Optimization of the Biaryl Aglycone for FimH Lectin Binding Affinity and Efficacy in the Treatment of Chronic UTI. ChemMedChem. 2016 Feb;11(4):367-73. doi: 10.1002/cmdc.201600006. Epub 2016 Jan, 26. PMID:26812660 doi:http://dx.doi.org/10.1002/cmdc.201600006
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