6G2R

Crystal structure of FimH in complex with a tetraflourinated biphenyl alpha D-mannoside

Summary for 6G2R

• Entry DOI: 10.2210/pdb6g2r/pdb
• Descriptor: Type 1 fimbrin D-mannose specific adhesin, 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, SULFATE ION, ... (5 entities in total)
• Functional Keywords: type i pilus, catch-bond, cell adhesion, lectin, upec, infection, mannose
• Biological source: Escherichia coli (strain K12)
• Total number of polymer chains: 2
• Total formula weight: 35095.55

Authors

Jakob, R.P.,Schoenemann, W.,Cramer, J.,Muehlethaler, T.,Daetwyler, P.,Zihlmann, P.,Fiege, B.,Sager, C.P.,Smiesko, M.,Rabbani, S.,Eris, D.,Schwardt, O.,Maier, T.,Ernst, B. (deposition date: 2018-03-23, release date: 2019-03-20, Last modification date: 2024-11-06)

Primary citation

Schonemann, W.,Cramer, J.,Muhlethaler, T.,Fiege, B.,Silbermann, M.,Rabbani, S.,Datwyler, P.,Zihlmann, P.,Jakob, R.P.,Sager, C.P.,Smiesko, M.,Schwardt, O.,Maier, T.,Ernst, B.
Improvement of Aglycone pi-Stacking Yields Nanomolar to Sub-nanomolar FimH Antagonists.
Chemmedchem, 14:749-757, 2019

PubMed Abstract: 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 α-d-mannosides leads to compounds with perfect π-π stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to sub-nanomolar K 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 H, N-HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability.

PubMed: 30710416
DOI: 10.1002/cmdc.201900051

Experimental method

X-RAY DIFFRACTION (2.1 Å)