Studies on the molecular recognition of synthetic methyl beta-lactoside analogs by ricin, a cytotoxic plant lectin.
The binding of methyl beta-lactoside and of all possible monodeoxy derivatives of methyl beta-lactoside to the galactose-specific highly cytotoxin lectin ricin, has been investigated. The distribution of low-energy conformers of the disaccharide structures has been first determined using molecular-mechanics calculations and high-resolution NMR spectroscopy. The nuclear Overhauser enhancements and specific deshieldings observed are in agreement with a similar distribution of low-energy conformers for all studied compounds which may be described by a major conformer defined by phi (H1'-C1'-O1'-C4) and psi (C1'-O1'-C4-H4) torsion angles of 49 degrees and 5 degrees, respectively, with contribution of conformers with angles phi/psi 24 degrees/-59 degrees, 22 degrees/-32 degrees and 6 degrees/-44 degrees. Assuming that the disaccharides bind to the lectin in these preferred conformations, the apparent dissociation constants for the ricin-disaccharide complexes have been interpreted in terms of specific polar and nonpolar interactions. In agreement with X-ray data, the hydroxyl groups at positions 3, 4 and 6 of the beta-D-galactopyranose moiety appear as key polar groups in the interaction with ricin. These results are in contrast to previous results which have established that position 6 is not involved in lectin binding. An important nonpolar interaction involving position 3 of the beta-D-glucopyranose moiety, seems to be operative. The distribution of low-energy conformers of these disaccharide structures permits this interaction to take place with the hydroxyl group at this position intramolecularly bonded, thus rendering this region of the molecule more lipophylic in character for acceptance into nonpolar regions of the combining site.
Rivera-Sagredo
A
A
Instituto de Química Orgánica, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Solis
D
D
Diaz-Mauriño
T
T
Jiménez-Barbero
J
J
Martín-Lomas
M
M
D001665:Binding Sites; D002236:Carbohydrate Conformation; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008759:Methylglycosides / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D012276:Ricin; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D008759:Methylglycosides; C034207:methyl lactoside; D012276:Ricin