Thermodynamic Penalty Arising from Burial of a Ligand Polar Group Within a Hydrophobic Pocket of a Protein Receptor

Barratt, Elizabeth; Bronowska, Agnieszka K.; Vondrášek, Jiřı́; Černý, Jiří; Bingham, Richard J.; Phillips, Simon E. V.; Homans, Steve W.

doi:10.1016/j.jmb.2006.07.067

Cited by 38 publications

(46 citation statements)

References 35 publications

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“…Surprisingly, global thermodynamics data obtained for pyrazine ligands (Barratt et al 2004) and alcohols (Barratt et al, 2006) showed that binding is driven by favourable enthalpic contributions, rather than the classical hydrophobic effect. The only hydrogen bond that could be formed between a ligand and the protein binding site involved the hydroxyl group of tyrosine Y120.…”

Section: Calorimetric Studies Of Mupmentioning

confidence: 99%

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Thermodynamics of Ligand-Protein Interactions: Implications for Molecular Design

Bronowska¹

2011

Thermodynamics - Interaction Studies - Solids, Liquids and Gases

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Section: Calorimetric Studies Of Mupmentioning

confidence: 99%

“…examined, as it is likely to vary considerably from one ligand-protein system to another one (Barratt et al, 2005(Barratt et al, , 2006. Regarding weak hydrogen bonds, the most prominent donor is the CH group.…”

Section: Van Der Waals Interactionsmentioning

confidence: 99%

Thermodynamics of Ligand-Protein Interactions: Implications for Molecular Design

Bronowska¹

2011

Thermodynamics - Interaction Studies - Solids, Liquids and Gases

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“…24 z We note that all MUP structures, including those presented here, have been determined at pH 4.8-7.2. 21,23,24,[26][27][28][29][30][31][32] The pK a of the conjugate acid of thiazole and pyrazine derivatives is around pH 2, 38,39 thus, the sp2 hybridized nitrogen is less likely to be protonated at the pH of the experiments than is a Glu residue. To satisfy hydrogen bonding potential, we show E118 as protonated at OE2 in the figures.…”

Section: Ligand Coordination In Mup-ivmentioning

confidence: 99%

“…20,26,27,29,31,40,41 When compared with MUP-I, SBT binding to MUP-IV is characterized by a more favorable enthalpy (by 5 kcal/mol) and less favorable entropy (by 21 cal/mol/K). 20 From the known difference in affinities of MUP-I and MUP-IV for SBT, 20 we can calculate a DDG of À1.9 kcal/mol in favor of binding to MUP-IV, which is within the range expected for hydrogen bonding interactions.…”

Section: Implications For Thermodynamics Of Bindingmentioning

confidence: 99%

“…22 X-ray and NMR structures of MUP-I and MUP-II have been determined in the presence of SBT 23,24 as well as other ligands. [24][25][26][27][28][29][30][31][32] However, until now, there have been no published structures of a group 4 isoform. We have determined the X-ray crystal structures of MUP-IV in complex with three mouse pheromones to examine the structural basis of ligand binding specificity.…”

Section: Introductionmentioning

confidence: 99%

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High resolution X‐ray structures of mouse major urinary protein nasal isoform in complex with pheromones

et al. 2010

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In mice, the major urinary proteins (MUP) play a key role in pheromonal communication by binding and transporting semiochemicals. MUP-IV is the only isoform known to be expressed in the vomeronasal mucosa. In comparison with the MUP isoforms that are abundantly excreted in the urine, MUP-IV is highly specific for the male mouse pheromone 2-sec-butyl-4,5-dihydrothiazole (SBT). To examine the structural basis of this ligand preference, we determined the X-ray crystal structure of MUP-IV bound to three mouse pheromones: SBT, 2,5-dimethylpyrazine, and 2-heptanone. We also obtained the structure of MUP-IV with 2-ethylhexanol bound in the cavity. These four structures show that relative to the major excreted MUP isoforms, three amino acid substitutions within the binding calyx impact ligand coordination. The F103 for A along with F54 for L result in a smaller cavity, potentially creating a more closely packed environment for the ligand. The E118 for G substitution introduces a charged group into a hydrophobic environment. The sidechain of E118 is observed to hydrogen bond to polar groups on all four ligands with nearly the same geometry as seen for the water-mediated hydrogen bond network in the MUP-I and MUP-II crystal structures. These differences in cavity size and interactions between the protein and ligand are likely to contribute to the observed specificity of MUP-IV.

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Hydrophobic Association and Volume‐Confined Water Molecules

Baron¹,

Setny²,

McCammon³

2012

Protein‐Ligand Interactions

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Thermodynamic Penalty Arising from Burial of a Ligand Polar Group Within a Hydrophobic Pocket of a Protein Receptor

Cited by 38 publications

References 35 publications

Thermodynamics of Ligand-Protein Interactions: Implications for Molecular Design

Thermodynamics of Ligand-Protein Interactions: Implications for Molecular Design

High resolution X‐ray structures of mouse major urinary protein nasal isoform in complex with pheromones

Hydrophobic Association and Volume‐Confined Water Molecules

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