The Tyrosine Gate of the Bacterial Lectin FimH : a Conformational Analysis by NMR Spectroscopy and X-ray Crystallography

Fiege, Brigitte and Rabbani, Said and Preston, Roland C. and Jakob, Roman P. and Zihlmann, Pascal and Schwardt, Oliver and Jiang, Xiaohua and Maier, Timm and Ernst, Beat. (2015) The Tyrosine Gate of the Bacterial Lectin FimH : a Conformational Analysis by NMR Spectroscopy and X-ray Crystallography. ChemBioChem, 16 (8). pp. 1235-1246.

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Official URL: http://edoc.unibas.ch/dok/A6381805

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Urinary tract infections caused by uropathogenic E. coli are among the most prevalent infectious diseases. The mannose-specific lectin FimH mediates the adhesion of the bacteria to the urothelium, thus enabling host cell invasion and recurrent infections. An attractive alternative to antibiotic treatment is the development of FimH antagonists that mimic the physiological ligand. A large variety of candidate drugs have been developed and characterized by means of in vitro studies and animal models. Here we present the X-ray co-crystal structures of FimH with members of four antagonist classes. In three of these cases no structural data had previously been available. We used NMR spectroscopy to characterize FimH-antagonist interactions further by chemical shift perturbation. The analysis allowed a clear determination of the conformation of the tyrosine gate motif that is crucial for the interaction with aglycone moieties and was not obvious from X-ray structural data alone. Finally, ITC experiments provided insight into the thermodynamics of antagonist binding. In conjunction with the structural information from X-ray and NMR experiments the results provide a mechanism for the often-observed enthalpy-entropy compensation of FimH antagonists that plays a role in fine-tuning of the interaction.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Maier)
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Ehemalige Einheiten Pharmazie > Molekulare Pharmazie (Ernst)
UniBasel Contributors:Rabbani, Said and Schwardt, Oliver and Preston, Roland and Jiang, Xiaohua and Maier, Timm and Jakob, Roman Peter and Zihlmann, Pascal and Fiege, Brigitte and Ernst, Beat
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:28 Nov 2017 11:18
Deposited On:05 Jun 2015 08:53

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