Recognition of selected monosaccharides by Pseudomonas aeruginosa Lectin II analyzed by molecular dynamics and free energy calculations

Mishra, Navnit Kumar; Křı́ž, Zdeněk; Wimmerová, Michaela; Koča, Jaroslav

doi:10.1016/j.carres.2010.04.021

Cited by 17 publications

(23 citation statements)

References 55 publications

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“…This phenomenon could originate from the additional methyl group in 4 , which stabilizes the complex by van der Waals interaction with the protein. The importance of the van der Waals interaction of fucose with Thr45 in LecB has previously been analyzed by Mishra et al [52] In the same study, a similar flexibility of loops in the carbohydrate recognition domain, as observed here for the low affinity ligand, was reported in absence of the high affinity ligand fucose. Although the conformation of LecB is generally conserved in the low-temperature crystal structures deposited in the protein data bank, flexibility at ambient conditions seems thus reasonable supporting our observations.…”

Section: Resultssupporting

confidence: 82%

A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB

2014

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The rise of resistances against antibiotics in bacteria is a major threat for public health and demands the development of novel antibacterial therapies. Infections with Pseudomonas aeruginosa are a severe problem for hospitalized patients and for patients suffering from cystic fibrosis. These bacteria can form biofilms and thereby increase their resistance towards antibiotics. The bacterial lectin LecB was shown to be necessary for biofilm formation and the inhibition with its carbohydrate ligands resulted in reduced amounts of biofilm. The natural ligands for LecB are glycosides of d-mannose and l-fucose, the latter displaying an unusual strong affinity. Interestingly, although mannosides are much weaker ligands for LecB, they do form an additional hydrogen bond with the protein in the crystal structure. To analyze the individual contributions of the methyl group in fucosides and the hydroxymethyl group in mannosides to the binding, we designed and synthesized derivatives of these saccharides. We report glycomimetic inhibitors that dissect the individual interactions of their saccharide precursors with LecB and give insight into the biophysics of binding by LecB. Furthermore, theoretical calculations supported by experimental thermodynamic data suggest a perturbed hydrogen bonding network for mannose derivatives as molecular basis for the selectivity of LecB for fucosides. Knowledge gained on the mode of interaction of LecB with its ligands at ambient conditions will be useful for future drug design.

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Section: Resultssupporting

confidence: 82%

A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB

2014

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“…Antigens with terminal fucose epitopes, including Le b and Le Y , are relatively inactive (181). Mapping studies indicate that PA-IIL binds fucose along a shallow groove and is highly dependent on van der Waals interactions between PA-IIA and the C-5 methyl group of fucose (182). The hydroxyl groups on C-2, C-3, and C-4 of fucose also contribute to binding through electrostatic interactions with calcium ions, water, and PA-IIL.…”

Section: Pseudomonas Aeruginosamentioning

confidence: 99%

Blood Groups in Infection and Host Susceptibility

2015

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SUMMARY Blood group antigens represent polymorphic traits inherited among individuals and populations. At present, there are 34 recognized human blood groups and hundreds of individual blood group antigens and alleles. Differences in blood group antigen expression can increase or decrease host susceptibility to many infections. Blood groups can play a direct role in infection by serving as receptors and/or coreceptors for microorganisms, parasites, and viruses. In addition, many blood group antigens facilitate intracellular uptake, signal transduction, or adhesion through the organization of membrane microdomains. Several blood groups can modify the innate immune response to infection. Several distinct phenotypes associated with increased host resistance to malaria are overrepresented in populations living in areas where malaria is endemic, as a result of evolutionary pressures. Microorganisms can also stimulate antibodies against blood group antigens, including ABO, T, and Kell. Finally, there is a symbiotic relationship between blood group expression and maturation of the gastrointestinal microbiome.

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“…Molecular docking studies of fucose and fucose-containing oligosaccharides have been published using a variety of computational approaches, in protein targets such as human lectins [28], [29], antibodies [30], [31] or virus capsid proteins [32]. Molecular docking calculations of fucose and methyl-fucoside in bacterial lectins were also reported even though the presence of calcium ions in some of the binding sites was computationally challenging [33]–[37].…”

Section: Introductionmentioning

confidence: 99%

Deciphering the Glycan Preference of Bacterial Lectins by Glycan Array and Molecular Docking with Validation by Microcalorimetry and Crystallography

Topin

Arnaud²,

Sarkar³

et al. 2013

PLoS ONE

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Recent advances in glycobiology revealed the essential role of lectins for deciphering the glycocode by specific recognition of carbohydrates. Integrated multiscale approaches are needed for characterizing lectin specificity: combining on one hand high-throughput analysis by glycan array experiments and systematic molecular docking of oligosaccharide libraries and on the other hand detailed analysis of the lectin/oligosaccharide interaction by x-ray crystallography, microcalorimetry and free energy calculations. The lectins LecB from Pseudomonas aeruginosa and BambL from Burkholderia ambifaria are part of the virulence factors used by the pathogenic bacteria to invade the targeted host. These two lectins are not related but both recognize fucosylated oligosaccharides such as the histo-blood group oligosaccharides of the ABH(O) and Lewis epitopes. The specificities were characterized using semi-quantitative data from glycan array and analyzed by molecular docking with the Glide software. Reliable prediction of protein/oligosaccharide structures could be obtained as validated by existing crystal structures of complexes. Additionally, the crystal structure of BambL/Lewis x was determined at 1.6 Å resolution, which confirms that Lewis x has to adopt a high-energy conformation so as to bind to this lectin. Free energies of binding were calculated using a procedure combining the Glide docking protocol followed by free energy rescoring with the Prime/Molecular Mechanics Generalized Born Surface Area (MM-GBSA) method. The calculated data were in reasonable agreement with experimental free energies of binding obtained by titration microcalorimetry. The established predictive protocol is proposed to rationalize large sets of data such as glycan arrays and to help in lead discovery projects based on such high throughput technology.

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Recognition of selected monosaccharides by Pseudomonas aeruginosa Lectin II analyzed by molecular dynamics and free energy calculations

Cited by 17 publications

References 55 publications

A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB

A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB

Blood Groups in Infection and Host Susceptibility

Deciphering the Glycan Preference of Bacterial Lectins by Glycan Array and Molecular Docking with Validation by Microcalorimetry and Crystallography

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