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4cst

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Revision as of 17:08, 2 January 2017

Crystal structure of FimH in complex with 3'-Chloro-4'-(alpha-D-mannopyranosyloxy)-biphenyl-4-carbonitrile

Structural highlights

4cst is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	4css, 4csy
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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. FimH Antagonists: Bioisosteres To Improve the in Vitro and in Vivo PK/PD Profile. J Med Chem. 2015 Feb 20. PMID:25666045 doi:http://dx.doi.org/10.1021/jm501524q

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4cst"

@@ Line 1: / Line 1: @@
 ==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]] 1.10&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CWK:3-CHLORO-4-(ALPHA-D-MANNOPYRANOSYLOXY)BIPHENYL-4-CARBONITRILE'>CWK</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4css|4css]], [[4csy|4csy]]</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=4cst FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cst OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4cst RCSB], [http://www.ebi.ac.uk/pdbsum/4cst PDBsum]</span></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=4cst FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cst OCA], [http://pdbe.org/4cst PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4cst RCSB], [http://www.ebi.ac.uk/pdbsum/4cst PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4cst ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4cst" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4cst

From Proteopedia

Revision as of 17:08, 2 January 2017

Crystal structure of FimH in complex with 3'-Chloro-4'-(alpha-D-mannopyranosyloxy)-biphenyl-4-carbonitrile

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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