6grn

Publication Abstract from PubMed

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 having 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, like for its enantiomer, because of hydrogen bond donation replacing the corresponding ones from hydroxyl groups in glucosyl residues of the natural substrate.

Enantioselective Binding of Propranolol and Analogues thereof to Cellobiohydrolase Cel7A.,Hamark C, Pendrill R, Landstrom J, Dotson Fagerstrom A, Sandgren M, Stahlberg J, Widmalm G Chemistry. 2018 Sep 26. doi: 10.1002/chem.201803104. PMID:30255965^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.