Orthogonal ligands

Copper(I) tends towards a tetrahedral coordination geometry in complexes. With 2,2 -bipyr-idine as a chelate ligand a distorted tetrahedral coordination with almost orthogonal ligands results. 2,2 -Bipyridine oligomers with flexible 6,6 -links therefore form double helices with two 2,2 -bipyridine units per copper(I) ion (J. M. Lehn, 1987,1988). J. M. Lehn (1990 U. Koert, 1990) has also prepared such helicates with nucleosides, e.g., thymidine, covalently attached to suitable spacers to obtain water-soluble double helix complexes, so-called inverted DNA , with internal positive charges and external nucleic bases. Cooperative effects lead preferentially to two identical strands in these helicates when copper(I) ions are added to a mixture of two different homooligomers. 

David Corey s team has also employed this approach, termed engineered orthogonal ligand-receptor pairs , in studies of retinoid x receptor to find near drugs . These near drugs are chemical tools used to discern the biology of the retinoid x receptors [23],... 

X-ray Crystallography in the Development of Orthogonal Ligand-Receptor Pairs... 

Fig. 8.1 Schematic diagram showing how a naturally occurring small molecule ligand-protein interaction is changed to create an orthogonal ligand-receptor pair.

Orthogonal ligand-receptor pairs have multiple applications for basic cellular and biochemical research. They also have practical applications that could soon be in use in the pharmaceutical and biotechnology industries. 

There are many examples in the literature of using binding pocket mutations to make orthogonal ligand-receptor pairs. For the purpose of brevity, the emphasis of this chapter will be on nudear receptor orthogonal ligand-receptor pairs. 

Natural variations in nuclear receptors reinforce the idea that nuclear receptors are good candidates for the creation of orthogonal ligand-receptor pairs. For example, the human retinoic acid receptor (RAR) has three subtypes RARa, RAR/ and RARy. These three subtypes differ at 87 amino acids but have only three divergent residues in the binding pocket [11] (Tab. 8.1). However, these three divergent residues are responsible for different binding profiles of synthetic retinoids... 

Fig. 8.9 The synthetic near drug LG335 is the orthogonal ligand in an orthogonal ligand-receptor pair created from the nuclear receptor RXR-a.

I 8 X-ray Crystallography in the Development of Orthogonal Ligand-Receptor Pairs Tab. 8.2 AspAT residues shortest distance to binding pocket. 

Fig. 8.14 The synthetic orthogonal ligand N -benzyl AlCAR triphosphate does not bind the wild type p38, but can be used as a substrate by the T106C variant.

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