7AYN

Crystal structure of the lectin domain of the FimH variant Arg98Ala, in complex with Methyl 3-chloro-4-D-mannopyranosyloxy-3-biphenylcarboxylate

Summary for 7AYN

• Entry DOI: 10.2210/pdb7ayn/pdb
• Descriptor: Type 1 fimbrin D-mannose specific adhesin, methyl 3-[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]benzoate, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: adhesin, fimh, upec, bladder infection, carbohydrate, lectin, cell adhesion
• Biological source: Escherichia coli K12
• Total number of polymer chains: 4
• Total formula weight: 69270.43

Authors

Jakob, R.P.,Tomasic, T.,Rabbani, S.,Reisner, A.,Jakopin, Z.,Maier, T.,Ernst, B.,Anderluh, M. (deposition date: 2020-11-12, release date: 2020-12-23, Last modification date: 2024-01-31)

Primary citation

Tomasic, T.,Rabbani, S.,Jakob, R.P.,Reisner, A.,Jakopin, Z.,Maier, T.,Ernst, B.,Anderluh, M.
Does targeting Arg98 of FimH lead to high affinity antagonists?
Eur.J.Med.Chem., 211:113093-113093, 2020

PubMed Abstract: Bacterial resistance has become an important challenge in the treatment of urinary tract infections. The underlying resistance mechanisms can most likely be circumvented with an antiadhesive approach, antagonizing the lectin FimH located at the tip of fimbriae of uropathogenic E. coli. Here we report on a novel series of FimH antagonists based on the 1-(α-d-mannopyranosyl)-4-phenyl-1,2,3-triazole scaffold, designed to incorporate carboxylic acid or ester functions to interact with FimH Arg98. The most potent representative of the series, ester 11e, displayed a K value of 7.6 nM for the lectin domain of FimH with a general conclusion that all esters outperform carboxylates in terms of affinity. Surprisingly, all compounds from this new series exhibited improved binding affinities also for the R98A mutant, indicating another possible interaction contributing to binding. Our study on 1-(α-d-mannopyranosyl)-4-phenyl-1,2,3-triazole-based FimH antagonists offers proof that targeting Arg98 side chain by a "chemical common sense", i.e. by introduction of the acidic moiety to form ionic bond with Arg98 is most likely unsuitable approach to boost FimH antagonists' potency.

PubMed: 33340913
DOI: 10.1016/j.ejmech.2020.113093

Experimental method

X-RAY DIFFRACTION (1.42 Å)