6qge
From Proteopedia
Galectin-3C in complex with a pair of enantiomeric ligands: S enantiomer
Structural highlights
Function[LEG3_HUMAN] Galactose-specific lectin which binds IgE. May mediate with the alpha-3, beta-1 integrin the stimulation by CSPG4 of endothelial cells migration. Together with DMBT1, required for terminal differentiation of columnar epithelial cells during early embryogenesis (By similarity). In the nucleus: acts as a pre-mRNA splicing factor. Involved in acute inflammatory responses including neutrophil activation and adhesion, chemoattraction of monocytes macrophages, opsonization of apoptotic neutrophils, and activation of mast cells.[1] [2] [3] Publication Abstract from PubMedUnderstanding the driving forces underlying molecular recognition is of fundamental importance in chemistry and biology. The challenge is to unravel the binding thermodynamics into separate contributions and to interpret these in molecular terms. Entropic contributions to the free energy of binding are particularly difficult to assess in this regard. Here we pinpoint the molecular determinants underlying differences in ligand affinity to the carbohydrate recognition domain of galectin-3, using a combination of isothermal titration calorimetry, X-ray crystallography, NMR relaxation, and molecular dynamics simulations followed by conformational entropy and grid inhomogeneous solvation theory (GIST) analyses. Using a pair of diastereomeric ligands that have essentially identical chemical potential in the unbound state, we reduced the problem of dissecting the thermodynamics to a comparison of the two protein-ligand complexes. While the free energies of binding are nearly equal for the R and S diastereomers, greater differences are observed for the enthalpy and entropy, which consequently exhibit compensatory behavior, DeltaDelta H degrees (R - S) = -5 +/- 1 kJ/mol and - TDeltaDelta S degrees (R - S) = 3 +/- 1 kJ/mol. NMR relaxation experiments and molecular dynamics simulations indicate that the protein in complex with the S-stereoisomer has greater conformational entropy than in the R-complex. GIST calculations reveal additional, but smaller, contributions from solvation entropy, again in favor of the S-complex. Thus, conformational entropy apparently dominates over solvation entropy in dictating the difference in the overall entropy of binding. This case highlights an interplay between conformational entropy and solvation entropy, pointing to both opportunities and challenges in drug design. Interplay between Conformational Entropy and Solvation Entropy in Protein-Ligand Binding.,Verteramo ML, Stenstrom O, Ignjatovic MM, Caldararu O, Olsson MA, Manzoni F, Leffler H, Oksanen E, Logan DT, Nilsson UJ, Ryde U, Akke M J Am Chem Soc. 2019 Feb 6;141(5):2012-2026. doi: 10.1021/jacs.8b11099. Epub 2019 , Jan 23. PMID:30618244[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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