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Enantioselective Binding of Propranolol and Analogues Thereof to Cellobiohydrolase Cel7A

Hamark, Christoffer ; Pendrill, Robert ; Landström, Jens ; Dotson Fagerström, Alexandra LU ; Sandgren, Mats ; Ståhlberg, Jerry and Widmalm, Göran (2018) In Chemistry - A European Journal 24(68). p.17975-17985
Abstract

At the catalytic site for the hydrolysis of cellulose the enzyme cellobiohydrolase Cel7A binds the enantiomers of the adrenergic beta-blocker propranolol with different selectivity. Methyl-to-hydroxymethyl group modifications of propranolol, which result in higher affinity and improved selectivity, were herein studied by 1H,1H and 1H,13C scalar spin–spin coupling constants as well as utilizing the nuclear Overhauser effect (NOE) in conjunction with molecular dynamics simulations of the ligands per se, which showed the presence of all-antiperiplanar conformations, except for the one containing a vicinal oxygen–oxygen arrangement governed by the gauche effect. For the ligand–protein complexes... (More)

At the catalytic site for the hydrolysis of cellulose the enzyme cellobiohydrolase Cel7A binds the enantiomers of the adrenergic beta-blocker propranolol with different selectivity. Methyl-to-hydroxymethyl group modifications of propranolol, which result in higher affinity and improved selectivity, were herein studied by 1H,1H and 1H,13C scalar spin–spin coupling constants as well as utilizing the nuclear Overhauser effect (NOE) in conjunction with molecular dynamics simulations of the ligands per se, which showed the presence of all-antiperiplanar conformations, except for the one containing a vicinal oxygen–oxygen arrangement governed by the gauche effect. For the ligand–protein complexes investigated by NMR spectroscopy using, inter alia, transferred NOESY and saturation-transfer difference (STD) NMR experiments the S-isomers were shown to bind with a higher affinity and a conformation similar to that preferred in solution, in contrast to the R-isomer. The fact that the S-form of the propranolol enantiomer is pre-arranged for binding to the protein is also observed for a crystal structure of dihydroxy-(S)-propranolol and Cel7A presented herein. Whereas the binding of propranolol is entropy driven, the complexation with the dihydroxy analogue is anticipated to be favored also by an enthalpic term, such as for its enantiomer, that is, dihydroxy-(R)-propranolol, because hydrogen-bond donation replaces the corresponding bonding from hydroxyl groups in glucosyl residues of the natural substrate. In addition to a favorable entropy component, albeit lesser in magnitude, this represents an effect of enthalpy-to-entropy compensation in ligand–protein interactions.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
enzymes, ligand–protein interactions, NMR spectroscopy, nuclear Overhauser effect, propranolol
in
Chemistry - A European Journal
volume
24
issue
68
pages
17975 - 17985
publisher
Wiley Online Library
external identifiers
  • pmid:30255965
  • scopus:85056655533
ISSN
0947-6539
DOI
10.1002/chem.201803104
language
English
LU publication?
yes
id
2c5f1712-15bd-45e0-8812-2a161171a610
date added to LUP
2018-11-28 13:30:37
date last changed
2020-01-08 08:24:20
@article{2c5f1712-15bd-45e0-8812-2a161171a610,
  abstract     = {<p>At the catalytic site for the hydrolysis of cellulose the enzyme cellobiohydrolase Cel7A binds the enantiomers of the adrenergic beta-blocker propranolol with different selectivity. Methyl-to-hydroxymethyl group modifications of propranolol, which result in higher affinity and improved selectivity, were herein studied by <sup>1</sup>H,<sup>1</sup>H and <sup>1</sup>H,<sup>13</sup>C scalar spin–spin coupling constants as well as utilizing the nuclear Overhauser effect (NOE) in conjunction with molecular dynamics simulations of the ligands per se, which showed the presence of all-antiperiplanar conformations, except for the one containing a vicinal oxygen–oxygen arrangement governed by the gauche effect. For the ligand–protein complexes investigated by NMR spectroscopy using, inter alia, transferred NOESY and saturation-transfer difference (STD) NMR experiments the S-isomers were shown to bind with a higher affinity and a conformation similar to that preferred in solution, in contrast to the R-isomer. The fact that the S-form of the propranolol enantiomer is pre-arranged for binding to the protein is also observed for a crystal structure of dihydroxy-(S)-propranolol and Cel7A presented herein. Whereas the binding of propranolol is entropy driven, the complexation with the dihydroxy analogue is anticipated to be favored also by an enthalpic term, such as for its enantiomer, that is, dihydroxy-(R)-propranolol, because hydrogen-bond donation replaces the corresponding bonding from hydroxyl groups in glucosyl residues of the natural substrate. In addition to a favorable entropy component, albeit lesser in magnitude, this represents an effect of enthalpy-to-entropy compensation in ligand–protein interactions.</p>},
  author       = {Hamark, Christoffer and Pendrill, Robert and Landström, Jens and Dotson Fagerström, Alexandra and Sandgren, Mats and Ståhlberg, Jerry and Widmalm, Göran},
  issn         = {0947-6539},
  language     = {eng},
  month        = {12},
  number       = {68},
  pages        = {17975--17985},
  publisher    = {Wiley Online Library},
  series       = {Chemistry - A European Journal},
  title        = {Enantioselective Binding of Propranolol and Analogues Thereof to Cellobiohydrolase Cel7A},
  url          = {http://dx.doi.org/10.1002/chem.201803104},
  doi          = {10.1002/chem.201803104},
  volume       = {24},
  year         = {2018},
}