View source for 8usm


==FmlH Lectin Domain UTI89 - AM4085==
<StructureSection load='8usm' size='340' side='right'caption='[[8usm]], [[Resolution|resolution]] 1.63&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8usm]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8USM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8USM 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]] 1.63&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XC8:4-fluoro-6-(trifluoromethyl)[1,1-biphenyl]-2-yl+2-acetamido-2-deoxy-beta-D-galactopyranoside'>XC8</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=8usm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8usm OCA], [https://pdbe.org/8usm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8usm RCSB], [https://www.ebi.ac.uk/pdbsum/8usm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8usm ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/YDEQ_ECOLI YDEQ_ECOLI] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
FmlH, a bacterial adhesin of uropathogenic Escherichia coli (UPEC), has been shown to provide a fitness advantage in colonizing the bladder during chronic urinary tract infections (UTIs). Previously reported ortho-biphenyl glycosides based on betaGal and betaGalNAc have excellent binding affinity to FmlH and potently block binding to its natural carbohydrate receptor, but they lack oral bioavailability. In this paper, we outline studies where we have optimized compounds for improved pharmacokinetics, leading to the discovery of novel analogues with good oral bioavailability. We synthesized galactosides with the anomeric O-linker replaced with more stable S- and C-linked linkers. We also investigated modifications to the GalNAc sugar and modifications to the biphenyl aglycone. We identified GalNAc 69 with an IC(50) of 0.19 muM against FmlH and 53% oral bioavailability in mice. We also obtained a FimlH-bound X-ray structure of lead compound 69 (AM4085) which has potential as a new antivirulence therapeutic for UTIs.

Discovery of Orally Bioavailable FmlH Lectin Antagonists as Treatment for Urinary Tract Infections.,Maddirala AR, Tamadonfar K, Pinkner JS, Sanick D, Hultgren SJ, Janetka JW J Med Chem. 2024 Mar 14;67(5):3668-3678. doi: 10.1021/acs.jmedchem.3c02128. Epub , 2024 Feb 3. PMID:38308631<ref>PMID:38308631</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8usm" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli]]
[[Category: Large Structures]]
[[Category: Hultgren SJ]]
[[Category: Janetka JW]]
[[Category: Maddirala AR]]
[[Category: Pinkner JP]]
[[Category: Tamadonfar KO]]