4cst: Difference between revisions
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The | ==Crystal structure of FimH in complex with 3'-Chloro-4'-(alpha-D-mannopyranosyloxy)-biphenyl-4-carbonitrile== | ||
<StructureSection load='4cst' size='340' side='right'caption='[[4cst]], [[Resolution|resolution]] 1.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4cst]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CST OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CST FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.1Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CWK:3-CHLORO-4-(ALPHA-D-MANNOPYRANOSYLOXY)BIPHENYL-4-CARBONITRILE'>CWK</scene></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=4cst FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cst OCA], [https://pdbe.org/4cst PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cst RCSB], [https://www.ebi.ac.uk/pdbsum/4cst PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cst ProSAT]</span></td></tr> | |||
</table> | |||
== 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 == | |||
Urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli (UPEC), belong to the most prevalent infectious diseases worldwide. The attachment of UPEC to host cells is mediated by FimH, a mannose-binding adhesin at the tip of bacterial type 1 pili. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials. Therefore, new treatment strategies are urgently needed. Here, we describe the development of an orally available FimH antagonist. Starting from the carboxylate substituted biphenyl alpha-d-mannoside 9, affinity and the relevant pharmacokinetic parameters (solubility, permeability, renal excretion) were substantially improved by a bioisosteric approach. With 3'-chloro-4'-(alpha-d-mannopyranosyloxy)biphenyl-4-carbonitrile (10j) a FimH antagonist with an optimal in vitro PK/PD profile was identified. Orally applied, 10j was effective in a mouse model of UTI by reducing the bacterial load in the bladder by about 1000-fold. | |||
FimH Antagonists: Bioisosteres To Improve the in Vitro and in Vivo PK/PD Profile.,Kleeb S, Pang L, Mayer K, Eris D, Sigl A, Preston RC, Zihlmann P, Sharpe T, Jakob RP, Abgottspon D, Hutter AS, Scharenberg M, Jiang X, Navarra G, Rabbani S, Smiesko M, Ludin N, Bezencon J, Schwardt O, Maier T, Ernst B J Med Chem. 2015 Feb 20. PMID:25666045<ref>PMID:25666045</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4cst" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Adhesin 3D structures|Adhesin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Escherichia coli K-12]] | |||
[[Category: Large Structures]] | |||
[[Category: Abgottspon D]] | |||
[[Category: Eris D]] | |||
[[Category: Ernst B]] | |||
[[Category: Hutter A]] | |||
[[Category: Jakob RP]] | |||
[[Category: Jian X]] | |||
[[Category: Kleeb S]] | |||
[[Category: Luedin N]] | |||
[[Category: Maier T]] | |||
[[Category: Mayer K]] | |||
[[Category: Navarra G]] | |||
[[Category: Pang L]] | |||
[[Category: Preston RC]] | |||
[[Category: Rabbani S]] | |||
[[Category: Scharenberg M]] | |||
[[Category: Schwardt O]] | |||
[[Category: Sharpe T]] | |||
[[Category: Sigl A]] | |||
[[Category: Smiesko M]] | |||
[[Category: Zihlmann P]] | |||
Latest revision as of 15:15, 20 December 2023
Crystal structure of FimH in complex with 3'-Chloro-4'-(alpha-D-mannopyranosyloxy)-biphenyl-4-carbonitrileCrystal structure of FimH in complex with 3'-Chloro-4'-(alpha-D-mannopyranosyloxy)-biphenyl-4-carbonitrile
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 PubMedUrinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli (UPEC), belong to the most prevalent infectious diseases worldwide. The attachment of UPEC to host cells is mediated by FimH, a mannose-binding adhesin at the tip of bacterial type 1 pili. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials. Therefore, new treatment strategies are urgently needed. Here, we describe the development of an orally available FimH antagonist. Starting from the carboxylate substituted biphenyl alpha-d-mannoside 9, affinity and the relevant pharmacokinetic parameters (solubility, permeability, renal excretion) were substantially improved by a bioisosteric approach. With 3'-chloro-4'-(alpha-d-mannopyranosyloxy)biphenyl-4-carbonitrile (10j) a FimH antagonist with an optimal in vitro PK/PD profile was identified. Orally applied, 10j was effective in a mouse model of UTI by reducing the bacterial load in the bladder by about 1000-fold. FimH Antagonists: Bioisosteres To Improve the in Vitro and in Vivo PK/PD Profile.,Kleeb S, Pang L, Mayer K, Eris D, Sigl A, Preston RC, Zihlmann P, Sharpe T, Jakob RP, Abgottspon D, Hutter AS, Scharenberg M, Jiang X, Navarra G, Rabbani S, Smiesko M, Ludin N, Bezencon J, Schwardt O, Maier T, Ernst B J Med Chem. 2015 Feb 20. PMID:25666045[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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