title: Complexes of glucoamylase with maltoside heteroanalogues: bound ligand conformations by use of transferred NOE experiments and molecular modeling.
abstract: Transferred nuclear Overhauser effect (trNOE) experiments have been performed to investigate the conformations of the competitive inhibitors, methyl 5'-thio-4-N-alpha-maltoside 3a and methyl 5'-thio-4-S-alpha-maltoside 4 when bound to the catalytic subunit of the enzyme glucoamylase. These NMR data suggest that, although each of the free ligands populates two conformational families, both heteroanalogues are bound by the enzyme in conformations in the area of the global energy minimum. These conformations have been used as initial points for docking into the active site of the enzyme taken from a X-ray crystal structure of the related glucoamylase-D-gluco-dihydroacarbose 2 complex. Minimization of the resulting complexes has yielded structures for the bound complexes. Corroboration of the structures is provided by fast T(1)(rho)-relaxation effects for certain ligand protons as a result of close contacts with protons in the enzyme active site. The results auger well for the combined use of transferred NOE spectroscopy and molecular modeling based on X-ray crystal structures of complexes of suitable congeners for the rapid analysis of ligand-receptor interactions.
authors.affiliation: Institut für Chemie, Medizinische Universität zu Lübeck, Ratzeburger Allee 160, Lübeck 23538, Germany. thomas.weimar@chemie.mu-luebeck.de
authors.forename: T
authors.initials: T
authors.lastname: Weimar
authors.forename: B
authors.initials: B
authors.lastname: Stoffer
authors.forename: B
authors.initials: B
authors.lastname: Svensson
authors.forename: B M
authors.initials: BM
authors.lastname: Pinto
mesh_terms: D020909:Acarbose / Q000494:pharmacology; D001665:Binding Sites; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D005087:Glucan 1,4-alpha-Glucosidase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006027:Glycosides / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008757:Methylglucosides / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data
chemical_list: D006027:Glycosides; D008757:Methylglucosides; C075762:methyl 4-thio-alpha-maltoside; D005087:Glucan 1,4-alpha-Glucosidase; D020909:Acarbose