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Institute for Pheromone Research and Department of Chemistry, Indiana University, Bloomington, Indiana 47405-0001, USA
(RECEIVED June 8, 2004; FINAL REVISION September 5, 2004; ACCEPTED September 22, 2004)
The mouse pheromones (±)-2-sec-butyl-4,5-dihydrothiazole (SBT) and 6-hydroxy-6-methyl-3-heptanone (HMH) bind into an occluded hydrophobic cavity in the mouse major urinary protein (MUP-1). Although the ligands are structurally unrelated, in both cases binding is accompanied by formation of a similar buried, water-mediated hydrogen bond network between the ligand and several backbone and side chain groups on the protein. To investigate the energetic contribution of this hydrogen bond network to ligand binding, we have applied isothermal titration calorimetry to measure the binding thermodynamics using several MUP mutants and ligand analogs. Mutation of Tyr-120 to Phe, which disrupts a hydrogen bond from the phenolic hydroxyl group of Tyr-120 to one of the bound water molecules, results in a substantial loss of favorable binding enthalpy, which is partially compensated by a favorable change in binding entropy. A similar thermodynamic effect was observed when the hydrogen bonded nitrogen atom of the heterocyclic ligand was replaced by a methyne group. Several other modifications of the protein or ligand had smaller effects on the binding thermodynamics. The data provide supporting evidence for the role of the hydrogen bond network in stabilizing the complex.
Keywords: enthalpy; hydrogen bond; major urinary protein; pheromone; thermodynamics; water
Abbreviations: HEWL, hen egg white lysozyme • HMH, 6-hydroxy-6-methyl-3-heptanone • ITC, isothermal titration calorimetry • MCP, 1-methyl-1-cyclopentene • MF, 4,5-dihydro-2-methylfuran • MO, 2-methyl-oxazoline • MP, 2-methyl-1-pyrroline • MT, 2-methyl-4,5-dihydrothiazole • MUP, major urinary protein • SBT, (±)-2-sec-butyl-4,5-dihydrothiazole
Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.04912605.
Reprint requests to: Martin J. Stone or Milos V. Novotny, Department of Chemistry, Indiana University, Bloomington, IN 47405-0001, USA; e-mail: mastone{at}indiana.edu or novotny{at}indiana.edu; fax: (812) 855-8300.
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