2010
DOI: 10.1021/ja105852y
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Protein Flexibility and Conformational Entropy in Ligand Design Targeting the Carbohydrate Recognition Domain of Galectin-3

Abstract: Rational drug design is predicated on knowledge of the three-dimensional structure of the protein−ligand complex and the thermodynamics of ligand binding. Despite the fundamental importance of both enthalpy and entropy in driving ligand binding, the role of conformational entropy is rarely addressed in drug design. In this work, we have probed the conformational entropy and its relative contribution to the free energy of ligand binding to the carbohydrate recognition domain of galectin-3. Using a combination o… Show more

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Cited by 213 publications
(232 citation statements)
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References 115 publications
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“…In a study on the energetics of carbohydrate binding to the carbohydrate recognition domain of Galectin-3, Akke and co-workers made the surprising discovery that protein conformational fluctuations on the ps-to-ns time scale, probed with 15 N (Akke et al 1993b;Farrow et al 1994b;Hansen et al 2007Hansen et al , 2009) and 2 H spin relaxation (Millet et al 2002), are amplified in the ligand bound state relative to unbound states (Akke, 2012;Diehl et al 2010). This finding is at large with the, perhaps more intuitive, quenching of fast time scale motions in protein-ligand complexes as observed for instance for Adk (Shapiro et al 2000).…”
Section: Conformational Entropymentioning
confidence: 99%
“…In a study on the energetics of carbohydrate binding to the carbohydrate recognition domain of Galectin-3, Akke and co-workers made the surprising discovery that protein conformational fluctuations on the ps-to-ns time scale, probed with 15 N (Akke et al 1993b;Farrow et al 1994b;Hansen et al 2007Hansen et al , 2009) and 2 H spin relaxation (Millet et al 2002), are amplified in the ligand bound state relative to unbound states (Akke, 2012;Diehl et al 2010). This finding is at large with the, perhaps more intuitive, quenching of fast time scale motions in protein-ligand complexes as observed for instance for Adk (Shapiro et al 2000).…”
Section: Conformational Entropymentioning
confidence: 99%
“…This protein contains four His residues, His158, 208, 217, and 223. We started by performing an analysis of the solvent accessibility and hydrogen-bond pattern of these residues in the crystal structure [9]. The results are shown in Table 4 and Figure 3.…”
Section: Galectin-3mentioning
confidence: 99%
“…Results of an analysis of the surroundings of the His residues in galectin-3 [9]. The solvent accessibility (SA; cf.…”
mentioning
confidence: 99%
“…Galectin-3 is found under different forms: 1) the primary form contains a polypeptidic chain of 250 aminoacids; the N-terminal domain has 120 aminoacids and allows the formation of oligomers, as well as the expression of the molecule on the cell membrane [20]; the collagen-alpha-like medial sequence includes proline and glycine, and can be cleaved by metaloproteinases [22]; the C-terminal domain contains 130 aminoacids [23]; 2) in the secondary form, CRD is organized as a β-pleated sheet, with antiparallel organization of polypeptidic chains which render it flexible and resilient to stretch [24]; 3) a globular tertiary form; 4) a quaternary form that may be either mono-or multimeric according to the concentration: when concentrations are low, monomers are more likely to occur, promoting intercellular adhesion, by binding and blocking integrins on other cells; when concentrations are higher, multimers are formed, mediating intercellular adhesion.…”
Section: Galectin-3: Biological Background and Functionmentioning
confidence: 99%