Comparative stereochemical analysis of glucose-binding proteins for rational design of glucose-specific agents.
There is a need for synthesizing glucose-sensitive molecules which can be used in glucose sensors and self-regulating insulin delivery devices. Currently, glucose-sensitive proteins, such as glucose oxidase and concanavalin A (Con-A), are used for detecting glucose molecules. For long-term in vivo applications, it is necessary to synthesize non-proteineous glucose-sensitive molecules which are biocompatible, nontoxic, cost-effective, and independent of environmental factors such as pH, ionic strength, or the presence of divalent cations. As a first step toward synthesizing glucose sensitive molecules, we have compared glucose-binding sites of four different types of glucose-binding proteins. They are human beta-cell glucokinase, D-xylose isomerase, lectins (Lathyrus ochrus isolectin I and Con-A), and glucose/galactose binding protein. Analysis of the glucose-binding sites of their 3-dimensional crystal structures showed that the hydrogen bonds between the hydroxyl groups of glucose and a few types of amino acid residues of proteins provided the main attraction. In some cases, the same atom was involved in multiple hydrogen bonds. Hydrophobic interactions between the pyranose ring of glucose and aromatic rings of hydrophobic amino acid residues also played an important role in the glucose specificity. A sandwich geometry was observed among the hydrophobic groups. This comparative stereochemical analysis suggests that a possible glucose binding site can be made by placing Asp and Asn around glucose for hydrogen bonding and Phe on both sides of glucose for hydrophobic interaction.
Li
T
T
Purdue University, School of Pharmacy, West Lafayette, IN 47907, USA.
Lee
H B
HB
Park
K
K
D001665:Binding Sites; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy; D004337:Drug Carriers; D015195:Drug Design; D005947:Glucose / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D009004:Monosaccharide Transport Proteins / Q000737:chemistry* / Q000378:metabolism
D004337:Drug Carriers; D009004:Monosaccharide Transport Proteins; D005947:Glucose