In combination with molecular genetics, structural biology also has used physical techniques—nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography—to its advantage in the study of proteins as drug targets, models for new drugs, and discovery tools (126). These two techniques can be used independently, or in concert, to determine the complete three-dimensional structure of proteins. Recent advances in NMR techniques, especially multidimensional heteronuclear studies, offer dramatic improvements in spectral resolution and interpretation (127,128).Iden-tification of differences in the results from comparative studies on the same protein can reveal important structural or dynamic information (129), possibly relevant to the design of synthetic ligands or inhibitors. Inclusion of such structural biology results into the more traditional synthesis-driven discovery paradigm has become a recognized and important component of drug design (130).
The variety of studies undertaken using these structural biology techniques spans the range of proteins of interest, from enzymes and hormones to receptors and antibodies. Re-combinantly produced reagents (accessible as either purified, soluble proteins or cell-surface expressed, functional enzymes and receptors) with potential application to drug discovery fall into a number of general categories: enzymes (with catalytic function), receptors (with signal transduction function), and binding proteins (with cellular adhesion properties). Rather than exhaustively catalog further examples, the next sections will highlight instances in which combinations of directed specific assays and structural biology studies have aided in non-protein drug discovery.
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