Orthogonal ligand-receptor pairs

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. 

Both of these strategies have broader applications than the kinase signaling pathways. Orthogonal ligand-receptor pairs could, theoretically, be made for any ligand-receptor pair. These pairs could then be used to study metabolic pathways and protein function, to identify smaD-molecule ligands and other applications. 

Orthogonal ligand-receptor pairs have only just begun to make an impact on basic research. The future holds much broader impacts in both basic research and practical applications in the pharmaceutical industry and biotechnology. X-ray crystallographic structures have formed the basis for many structure-based... 

Fig. 8.15 (A) X-ray crystal structure of PPl bound to Hck. Threonine-338 is analogous to phenyl-alanine-88 in cyclin-dependent kinase Cdc28. T88 was changed into a glycine in an attempt to create an orthogonal ligand-receptor pair. (B) Ligplot representation of PPl interaction with T338 [13]. Coordinates from lQCF[38j.

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