March 2006
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34 Reads
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7 Citations
ACS Symposium Series
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March 2006
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34 Reads
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7 Citations
ACS Symposium Series
November 2002
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41 Reads
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39 Citations
Chemistry - A European Journal
As a step to delineate a strategy of ligand design for cholera toxin (CT), NMR studies were performed on several mimics of the GM1 ganglioside oligosaccharide. The conformation of these analogues was investigated first in solution and then upon binding to cholera toxin by transferred nuclear Overhauser effect (TR-NOE) measurements. It was demonstrated that CT selects a conformation similar to the global minima of the free saccharides from the ensemble of presented conformations. No evidence of major conformational distortions was obtained, but one or two of the available conformers of the hydroxyacid side chain appear to be selected in the bound state. The NMR data were interpreted with the aid of computer models, generated and analyzed by using a combination of different approaches (MacroModels' MC/EM and MC/SD, Autodock, and GRID). Analysis of the NMR data supported by computational studies allowed us to interpret the experimental observations and to derive workable models of the ligand:toxin complexes. These models suggest that the higher affinity of the (R)-lactic acid derivative 3 may stem from lipophilic interactions with a hydrophobic area in the toxin binding site located in the vicinity of the sialic acid side chain binding region of the CT:GM1 complex, and formed by the side chain of Ile-58 and Lys-34. Thus, the models obtained have allowed us to make useful design suggestions for the improvement of ligand affinity.
October 2002
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3 Reads
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21 Citations
As a step to delineate a strategy of ligand design for cholera toxin (CT), NMR studies were performed on several mimics of the GM1 ganglioside oligosaccharide. The conformation of these analogues was investigated first in solution and then upon binding to cholera toxin by transferred nuclear Overhauser effect (TR-NOE) measurements. It was demonstrated that CT selects a conformation similar to the global minima of the free saccharides from the ensemble of presented conformations. No evidence of major conformational distortions was obtained, but one or two of the available conformers of the hydroxyacid side chain appear to be selected in the bound state. The NMR data were interpreted with the aid of computer models, generated and analyzed by using a combination of different approaches (MacroModels' MC/EM and MC/SD, Autodock, and GRID). Analysis of the NMR data supported by computational studies allowed us to interpret the experimental observations and to derive workable models of the ligand:toxin complexes. These models suggest that the higher affinity of the (R)-lactic acid derivative 3 may stem from lipophilic interactions with a hydrophobic area in the toxin binding site located in the vicinity of the sialic acid side chain binding region of the CT:GM1 complex, and formed by the side chain of Ile-58 and Lys-34. Thus, the models obtained have allowed us to make useful design suggestions for the improvement of ligand affinity.
June 2002
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27 Reads
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84 Citations
Journal of the American Chemical Society
We show that the conformational features of the molecular complexes of E. coli beta-galactosidase and O-glycosides may differ from those formed with closely related compounds in their chemical nature, such as C- and S-glycosyl analogues. In the particular case presented here, NMR and ab initio quantum mechanical results show that the 3D-shapes of the ligand/inhibitor within the enzyme binding site depend on the chemical nature of the compounds. In fact, they depend on the relative size of the stereoelectronic barriers for chair deformation or for rotation around Phi glycosidic linkage.
December 2001
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26 Reads
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36 Citations
Biochimica et Biophysica Acta
A hallmark of oligosaccharides is their often limited spatial flexibility, allowing them to access a distinct set of conformers in solution. Viewing each individual or even the complete ensemble of conformations as potential binding partner(s) for lectins in protein-carbohydrate interactions, it is pertinent to address the question on the characteristics of bound state conformation(s) in solution. Also, it is possible that entering the lectin's binding site distorts the low-energy topology of a glycosidic linkage. As a step to delineate the strategy of ligand selection for galactosides, a common physiological docking point, we have performed a NMR study on two non-homologous lectins showing identical monosaccharide specificity. Thus, the conformation of lactose analogues bound to bovine heart galectin-1 and to mistletoe lectin in solution has been determined by transferred nuclear Overhauser effect measurements. It is demonstrated that the lectins select the syn conformation of lactose and various structural analogues (Galbeta(1-->4)Xyl, Galbeta(1-->3)Xyl, Galbeta(1-->2)Xyl, and Galbeta(1-->3)Glc) from the ensemble of presented conformations. No evidence for conformational distortion was obtained. Docking of the analogues to the modeled binding sites furnishes explanations, in structural terms, for exclusive recognition of the syn conformer despite the non-homologous design of the binding sites.
January 2001
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10 Reads
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7 Citations
Journal of the Chemical Society Perkin Transactions 1
The conformational behaviour of N,N′-diacetyl-4-thiochitobiose (1) has been studied using a combination of NMR spectroscopy (NOE data) and molecular mechanics calculations. Analogies and differences with the natural compound N,N′-diacetylchitobiose (2) have been found. Moreover, the study of its bound conformation to the lectin wheat germ agglutinin has also been studied using TR-NOE experiments. A process of conformational selection is observed and only one of the conformers present in aqueous solution for the free state is bound by the lectin.
January 2001
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5 Reads
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25 Citations
Biochemistry
May 2000
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91 Reads
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51 Citations
The conformational behaviors of several nonhydrolyzable lactose analogs, namely Me α-thiolactoside, Me β-carbalactoside and Me β-carbaiminolactoside have been studied using a combination of NMR spectroscopy (J and NOE data) and mol. mechanics calcns. Analogies and differences with the natural compds. have been found. [on SciFinder(R)]
November 1999
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8 Reads
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63 Citations
Journal of the American Chemical Society
The conformational behavior of different aza-C-glycosides synthesized as glycosidase inhibitors has been studied using a combination of NMR spectroscopy (J and NOE data) and time-averaged restrained molecular dynamics calculations. The obtained results show that the population distribution of conformers around their pseudoglycosidic linkages is mainly controlled by 1,3-syn-diaxial interactions. Electrostatic effects slightly modulate the conformational equilibrium. This result is in contrast with that observed for O-glycosides. For these natural compounds, the conformational behavior around the glycosidic linkage Φ is mainly governed by the exo-anomeric effect. Experimentally based energy values for both the 1,3-syn-diaxial interactions and the stereoelectronic effect have been deduced. Finally, the inhibitory activity of these compounds has been tested again a variety of glycosidase enzymes.
... Furthermore, each single sugar-protein interaction is weak in nature and multivalency is required for molecular recognition processes to take place [3]. While polar hydroxyl groups participate in intermolecular hydrogen bonds to both water and the side chains of polar amino acids [4], the hydrophobic face of saccharides, composed by many nonpolar C-H groups, interacts with the aromatic residues of protein side chains [5]. Although the latter is much weaker, its existence has been sufficiently proven by different means. ...
March 2006
ACS Symposium Series
... This finding might reflect the presence of an ensemble of LC/A1 structures that was proposed to exist under physiological conditions 50 . It is also consistent with the presence of a molten globule-like structure of the catalytic domain at acidic pH, which is not observed in the context of the full-length toxin 51 . DARPin-F5 destabilizes LC/A1 at physiological pH but stabilizes the catalytic domain at acidic pH. ...
January 2001
Biochemistry
... Two exemplary approaches have been reported by replacing the glycosidic oxygen(s) of the native carbohydrate antigens with a sulfur or carbon atom to generate the corresponding enzyme-resistant S-glycosides [21][22][23][24][25][26][27][28] or C-glycosides. [29][30][31][32][33] For S-glycosides, studies have shown that although the CÀ S single bond is longer than the CÀ O bond, the CÀ SÀ C bond angle is significantly smaller than the CÀ OÀ C angle, which often results in very little differences between the position of the carbon atoms of the two types of glycosidic linkages; [34][35][36][37][38][39][40] studies have also shown that while S-glycosides are more flexible about the glycosidic linkage, they do sample similar conformational space of their O-glycoside counterparts. Thus geometrically, S-glycosides can effectively mimic their native O-glycosides when used as an antigen. ...
May 2000
... 50 The flexibility of these compounds results in an entropic cost during binding to proteins, even though the non-exo(Φ) conformation remains in most cases less stable, due to steric clash. 51,52 Thiasugars bear an endocyclic sulfur atom in place of the oxygen that makes them more flexible at the glycosidic linkages, due to stereoelectronic properties (weaker exoanomeric effect). In contrast to carbasugars, they retain the same overall conformation of the natural counterparts (exosyn(Φ) and exo-anti(Φ) are the most abundant conformations). ...
November 1999
Journal of the American Chemical Society
... A previous study of the binding of the Galα(1,4)Gal disaccharide (galabiose) to VAA also detected STD signals for the two Gal residues 40 . Different binding assays with various αand β-galactosides consistently indicated that VAA basically recognizes terminal Gal, the nature of the penultimate sugar unit and linkage configuration in general only slightly altering the binding affinity 34,35,41 . However, as a noticeable exception, a significantly higher affinity of VAA for galabiose was detected 42,43 , hinting at the establishment of additional contacts beyond the terminal α-Gal. ...
December 2001
Biochimica et Biophysica Acta
... As is known, enzymatic reactions usually undergo a binding-to-product process. 16,17 That is, the enzymesubstrate binding intermediate is first formed, which subsequently catalyzes the activation of substrate and generation of product. In consideration of the pathway, the efficiency of enzymatic reaction can be improved by structural matching. ...
June 2002
Journal of the American Chemical Society
... The molar ratio of polySia to the receptor peptides was 5:1 for these NMR experiments. The STD NMR experiments were performed as described [28,76] using a 10:1 ligand/receptor molar ratio for the interaction experiments, with 0.5, 1, and 2 s saturation times (by concatenation of 50 ms Gaussian pulses separated by 1 ms). ...
November 2002
Chemistry - A European Journal