title: The catalytic module of Cel7D from Phanerochaete chrysosporium as a chiral selector: structural studies of its complex with the beta blocker (R)-propranolol.
abstract: Previous investigations have shown that the major cellobiohydrolase of Phanerochaete chrysosporium, Cel7D (CBH 58), can be used to separate the enantiomers of a number of drugs, including adrenergic beta blockers such as propranolol. The structural basis of this enantioselectivity is explored here. A 1.5 A X-ray structure of the catalytic domain of Cel7D in complex with (R)-propranolol showed the ligand bound at the active site in glucosyl-binding subsites -1/+1. The catalytic residue Glu207 makes a strong charge-charge interaction with the secondary amine of (R)-propranolol; this is supported by a second interaction of the amine with the nearby Asp209. The aromatic naphthyl group stacks onto the indole ring of Trp373 (normally the glucosyl-binding platform of subsite +1). Other factors also contribute to good complementarity between the ligand and the substrate-binding cleft of the enzyme. Comparison with the previous structure of a related cellulase, Cel7A from Trichoderma reesei, in complex with (S)-propranolol strongly suggests that these enzymes will bind the (S)-enantiomer in a very similar manner, distinct from their mode of binding to (R)-propranolol. Tighter binding of both enzymes to the (S)-enantiomer is largely explained by two additional hydrogen-bonding interactions with its hydroxyl group. The distinct preference for the (R)-enantiomer is probably a consequence of structural differences near the naphthyl group of the ligand.
authors.affiliation: Department of Molecular Biology, Swedish University of Agricultural Sciences, Uppsala.
authors.forename: Inés G
authors.initials: IG
authors.lastname: Muñoz
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Mowbray
authors.forename: Jerry
authors.initials: J
authors.lastname: Ståhlberg
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000737:chemistry* / Q000302:isolation & purification; D002384:Catalysis; D043366:Cellulose 1,4-beta-Cellobiosidase / Q000737:chemistry*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008968:Molecular Conformation; D020075:Phanerochaete / Q000737:chemistry*; D011433:Propranolol / Q000737:chemistry* / Q000302:isolation & purification; D013237:Stereoisomerism; D014242:Trichoderma / Q000201:enzymology
chemical_list: D000319:Adrenergic beta-Antagonists; D011433:Propranolol; D043366:Cellulose 1,4-beta-Cellobiosidase