Thermodynamics of Binding of 2-Methoxy-3-isopropylpyrazine and 2-Methoxy-3-isobutylpyrazine to the Major Urinary Protein

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• 作者：Richard J. Bingham ; John B. C. Findlay ; Shih-Yang Hsieh ; Arnout P. Kalverda ; Alexandra Kjellberg ; Chiara Perazzolo ; Simon E. V. Phillips ; Kothandaraman Seshadri ; Chi H. Trinh ; W. Bruce Turnbull ; Geoff
• 刊名：Journal of the American Chemical Society
• 出版年：2004
• 出版时间：February 18, 2004
• 年：2004
• 卷：126
• 期：6
• 页码：1675 - 1681
• 全文大小：307K
• 年卷期：v.126,no.6(February 18, 2004)
• ISSN：1520-5126

文摘

In the present study we examine the thermodynamics of binding of two related pyrazine-derivedligands 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. Globalthermodynamics 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 theprotein backbone and side-chain residues in the vicinity of the binding pocket are partially offset by favorableentropic contributions at adjacent positions, suggesting a "conformational relay" mechanism wherebyincreased rigidity of residues on ligand binding are accompanied by increased conformational freedom ofside chains in adjacent positions. The principal driving force governing ligand affinity and specificity can beattributed to solvent-driven enthalpic effects from desolvation of the protein binding pocket.