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

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, Geoffrey Bodenhausen, Steve W. Homans

Research output: Contribution to journalArticle

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Abstract

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.

LanguageEnglish
Pages1675-1681
Number of pages7
JournalJournal of the American Chemical Society
Volume126
Issue number6
Early online date21 Jan 2004
DOIs
Publication statusPublished - 18 Feb 2004
Externally publishedYes

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Thermodynamics
Calorimetry
Ligands
Proteins
Titration
Pyrazines
X ray crystallography
X Ray Crystallography
Entropy
Protein Binding
Rigidity
Nuclear magnetic resonance
2-isobutyl-3-methoxypyrazine
2-isopropyl-3-methoxypyrazine
major urinary proteins

Cite this

Bingham, Richard J. ; Findlay, John B C ; Hsieh, Shih Yang ; Kalverda, Arnout P. ; Kjellberg, Alexandra ; Perazzolo, Chiara ; Phillips, Simon E V ; Seshadri, Kothandaraman ; Trinh, Chi H. ; Turnbull, W. Bruce ; Bodenhausen, Geoffrey ; Homans, Steve W. / Thermodynamics of Binding of 2-Methoxy-3-isopropylpyrazine and 2-Methoxy-3-isobutylpyrazine to the Major Urinary Protein. In: Journal of the American Chemical Society. 2004 ; Vol. 126, No. 6. pp. 1675-1681.
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abstract = "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.",
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Bingham, RJ, Findlay, JBC, Hsieh, SY, Kalverda, AP, Kjellberg, A, Perazzolo, C, Phillips, SEV, Seshadri, K, Trinh, CH, Turnbull, WB, Bodenhausen, G & Homans, SW 2004, 'Thermodynamics of Binding of 2-Methoxy-3-isopropylpyrazine and 2-Methoxy-3-isobutylpyrazine to the Major Urinary Protein', Journal of the American Chemical Society, vol. 126, no. 6, pp. 1675-1681. https://doi.org/10.1021/ja038461i

Thermodynamics of Binding of 2-Methoxy-3-isopropylpyrazine and 2-Methoxy-3-isobutylpyrazine to the Major Urinary Protein. / Bingham, Richard J.; Findlay, John B C; Hsieh, Shih Yang; Kalverda, Arnout P.; Kjellberg, Alexandra; Perazzolo, Chiara; Phillips, Simon E V; Seshadri, Kothandaraman; Trinh, Chi H.; Turnbull, W. Bruce; Bodenhausen, Geoffrey; Homans, Steve W.

In: Journal of the American Chemical Society, Vol. 126, No. 6, 18.02.2004, p. 1675-1681.

Research output: Contribution to journalArticle

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T1 - Thermodynamics of Binding of 2-Methoxy-3-isopropylpyrazine and 2-Methoxy-3-isobutylpyrazine to the Major Urinary Protein

AU - Bingham, Richard J.

AU - Findlay, John B C

AU - Hsieh, Shih Yang

AU - Kalverda, Arnout P.

AU - Kjellberg, Alexandra

AU - Perazzolo, Chiara

AU - Phillips, Simon E V

AU - Seshadri, Kothandaraman

AU - Trinh, Chi H.

AU - Turnbull, W. Bruce

AU - Bodenhausen, Geoffrey

AU - Homans, Steve W.

PY - 2004/2/18

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