5f3f: Difference between revisions
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==Crystal structure of para-biphenyl-2-methyl-3'-methyl amide mannoside bound to FimH lectin domain== | ==Crystal structure of para-biphenyl-2-methyl-3'-methyl amide mannoside bound to FimH lectin domain== | ||
<StructureSection load='5f3f' size='340' side='right' caption='[[5f3f]], [[Resolution|resolution]] 1.76Å' scene=''> | <StructureSection load='5f3f' size='340' side='right'caption='[[5f3f]], [[Resolution|resolution]] 1.76Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5f3f]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5F3F OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5f3f]] 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=5F3F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5F3F FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5US:3-[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}-METHYL-BENZAMIDE'>5US</scene> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.76Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5US:3-[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}-METHYL-BENZAMIDE'>5US</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5f3f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5f3f OCA], [https://pdbe.org/5f3f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5f3f RCSB], [https://www.ebi.ac.uk/pdbsum/5f3f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5f3f ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [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;"> | |||
== Publication Abstract from PubMed == | |||
Gram-negative uropathogenic Escherichia coli (UPEC) bacteria are a causative pathogen of urinary tract infections (UTIs). Previously developed antivirulence inhibitors of the type 1 pilus adhesin, FimH, demonstrated oral activity in animal models of UTI but were found to have limited compound exposure due to the metabolic instability of the O-glycosidic bond (O-mannosides). Herein, we disclose that compounds having the O-glycosidic bond replaced with carbon linkages had improved stability and inhibitory activity against FimH. We report on the design, synthesis, and in vivo evaluation of this promising new class of carbon-linked C-mannosides that show improved pharmacokinetic (PK) properties relative to O-mannosides. Interestingly, we found that FimH binding is stereospecifically modulated by hydroxyl substitution on the methylene linker, where the R-hydroxy isomer has a 60-fold increase in potency. This new class of C-mannoside antagonists have significantly increased compound exposure and, as a result, enhanced efficacy in mouse models of acute and chronic UTI. | |||
Antivirulence C-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary Tract Infections.,Mydock-McGrane L, Cusumano Z, Han Z, Binkley J, Kostakioti M, Hannan T, Pinkner JS, Klein R, Kalas V, Crowley J, Rath NP, Hultgren SJ, Janetka JW J Med Chem. 2016 Oct 27;59(20):9390-9408. doi: 10.1021/acs.jmedchem.6b00948. Epub , 2016 Oct 14. PMID:27689912<ref>PMID:27689912</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5f3f" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Adhesin 3D structures|Adhesin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Escherichia coli J96]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Hultgren SJ]] | ||
[[Category: | [[Category: Klein RD]] | ||
Latest revision as of 13:39, 30 October 2024
Crystal structure of para-biphenyl-2-methyl-3'-methyl amide mannoside bound to FimH lectin domainCrystal structure of para-biphenyl-2-methyl-3'-methyl amide mannoside bound to FimH lectin domain
Structural highlights
FunctionFIMH_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 PubMedGram-negative uropathogenic Escherichia coli (UPEC) bacteria are a causative pathogen of urinary tract infections (UTIs). Previously developed antivirulence inhibitors of the type 1 pilus adhesin, FimH, demonstrated oral activity in animal models of UTI but were found to have limited compound exposure due to the metabolic instability of the O-glycosidic bond (O-mannosides). Herein, we disclose that compounds having the O-glycosidic bond replaced with carbon linkages had improved stability and inhibitory activity against FimH. We report on the design, synthesis, and in vivo evaluation of this promising new class of carbon-linked C-mannosides that show improved pharmacokinetic (PK) properties relative to O-mannosides. Interestingly, we found that FimH binding is stereospecifically modulated by hydroxyl substitution on the methylene linker, where the R-hydroxy isomer has a 60-fold increase in potency. This new class of C-mannoside antagonists have significantly increased compound exposure and, as a result, enhanced efficacy in mouse models of acute and chronic UTI. Antivirulence C-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary Tract Infections.,Mydock-McGrane L, Cusumano Z, Han Z, Binkley J, Kostakioti M, Hannan T, Pinkner JS, Klein R, Kalas V, Crowley J, Rath NP, Hultgren SJ, Janetka JW J Med Chem. 2016 Oct 27;59(20):9390-9408. doi: 10.1021/acs.jmedchem.6b00948. Epub , 2016 Oct 14. PMID:27689912[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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