Protein Structures, Molecular Recognitions, and Functions 
This establishes a new motif for NADP/NAD-bind- 
ing oxidoreductases and the first structure of the 
superfamily of aldo-keto reductases. 
The substrate-binding site is located in an ex- 
tremely hydrophobic elliptical pocket at the car- 
boxyl-terminal end of the (8-barrel. The nicotin- 
amide group of the NADPH is at the bottom of the 
,deep pocket. Although the hydrophobic nature of 
the active site greatly favors aromatic (e.g., ste- 
roids) and apolar substrates, it is not wcW suited 
for binding of highly polar monosaccharides, 
which are believed to figure in the pathogenesis 
of diabetic complications. The determination of 
the structure of aldose reductase paves the way 
for rational design of specific inhibitors that 
might provide molecular understanding of the 
catalytic mechanism, as well as possible thera- 
peutic agents for the prevention of diabetic 
complications. 
Periplasmic Receptors for Active Transport 
and Chemotaxis 
The family of binding proteins that serve as ini- 
tial periplasmic receptors for bacterial active 
transport and chemotaxis continues to be a gold 
mine for detailed study of protein structure and 
molecular recognition of a variety of ligands. We 
continue to push the structure refinements of the 
seven different periplasmic receptors to much 
higher resolutions — the sulfate-binding protein 
(at 1 .7-A resolution), phosphate-binding protein 
(1.17 A), L-arabinose-binding protein (1.7 A), 
D-galactose/D-glucose-binding protein (1.5 A), 
maltodextrin-binding protein (1.7 A), leucine/ 
isoleucine/valine-binding protein (1.7 A), and 
leucine-specific-binding protein (1.7 A). 
Electrostatic Interactions in Molecular 
Recognition of Ligands 
Electrostatic interactions are among the key 
factors determining the structure and function of 
proteins. The refined structure of the liganded 
form of sulfate-binding protein shows that the 
bound sulfate dianion is completely buried and 
bound by hydrogen bonds and van der Waals con- 
tacts. The bound sulfate is adjacent to the amino 
termini of three helices and is coupled via a pep- 
tide unit to a positively charged His residue. Nev- 
ertheless, using site-directed mutagenesis and 
theoretical analysis, we have shown that helix 
macrodipoles and the His residue contribute al- 
most nothing to ligand fixation and charge com- 
pensation. It is the collection of local dipoles im- 
mediately surrounding the sulfate that is 
responsible for charge compensation. 
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