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Lookup NU author(s): Professor Steve Homans
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In the present study we examine the thermodynamics of binding of two related pyrazine-derived ligands to the major urinary protein, MUP-I, using a combination of isothermal titration calorimetry (ITC), X-ray crystallography, and NMR backbone 15N and methyl side-chain 2H relaxation measurements. Global thermodynamics data derived from ITC indicate that binding is driven by favorable enthalpic contributions, rather than the classical entropy-driven hydrophobic effect. Unfavorable entropic contributions from the protein backbone and side-chain residues in the vicinity of the binding pocket are partially offset by favorable entropic contributions at adjacent positions, suggesting a “conformational relay” mechanism whereby increased rigidity of residues on ligand binding are accompanied by increased conformational freedom of side chains in adjacent positions. The principal driving force governing ligand affinity and specificity can be attributed to solvent-driven enthalpic effects from desolvation of the protein binding pocket.
Author(s): Bingham RJ, Findlay JBC, Hsieh SY, Kalverda AP, Kjeliberg A, Perazzolo C, Phillips SEV, Seshadri K, Trinh CH, Turnbull WB, Bodenhausen G, Homans SW
Publication type: Article
Publication status: Published
Journal: Journal of the American Chemical Society
Year: 2004
Volume: 126
Issue: 6
Pages: 1675-1681
ISSN (print): 0002-7863
ISSN (electronic): 1943-2984
Publisher: American Chemical Society
URL: http://dx.doi.org/10.1021/ja038461i
DOI: 10.1021/ja038461i
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