6g2r: Difference between revisions
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==Crystal structure of FimH in complex with a tetraflourinated biphenyl alpha D-mannoside== | |||
<StructureSection load='6g2r' size='340' side='right'caption='[[6g2r]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6g2r]] is a 2 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=6G2R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6G2R 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]] 2.1Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EJK:4-[3-chloranyl-4-[(2~{R},3~{S},4~{S},5~{S},6~{R})-6-(hydroxymethyl)-3,4,5-tris(oxidanyl)oxan-2-yl]oxy-phenyl]-2,3,5,6-tetrakis(fluoranyl)benzenecarbonitrile'>EJK</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6g2r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g2r OCA], [https://pdbe.org/6g2r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6g2r RCSB], [https://www.ebi.ac.uk/pdbsum/6g2r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6g2r 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 == | |||
Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti-adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, has attracted considerable interest. FimH can adopt a low/medium-affinity state in the absence and a high-affinity state in the presence of shear forces. Until recently, mostly the high-affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low-affinity state. In this communication, we demonstrate that fluorination of biphenyl alpha-d-mannosides leads to compounds with perfect pi-pi stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to sub-nanomolar KD values for the low- and high-affinity states, respectively. The face-to-face alignment of the perfluorinated biphenyl group of FimH ligands and Tyr48 was confirmed by crystal structures as well as (1) H,(15) N-HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability. | |||
Improvement of Aglycone pi-Stacking Yields Nanomolar to Sub-nanomolar FimH Antagonists.,Schonemann W, Cramer J, Muhlethaler T, Fiege B, Silbermann M, Rabbani S, Datwyler P, Zihlmann P, Jakob RP, Sager CP, Smiesko M, Schwardt O, Maier T, Ernst B ChemMedChem. 2019 Feb 1. doi: 10.1002/cmdc.201900051. PMID:30710416<ref>PMID:30710416</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6g2r" 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: Cramer J]] | |||
[[Category: Daetwyler P]] | |||
[[Category: Eris D]] | |||
[[Category: Ernst B]] | |||
[[Category: Fiege B]] | |||
[[Category: Jakob RP]] | |||
[[Category: Maier T]] | |||
[[Category: Muehlethaler T]] | |||
[[Category: Rabbani S]] | |||
[[Category: Sager CP]] | |||
[[Category: Schoenemann W]] | |||
[[Category: Schwardt O]] | |||
[[Category: Smiesko M]] | |||
[[Category: Zihlmann P]] | |||