Domain hgand binding

Many natural protein hgands bind to their receptors via interactions of a specific area of the protein backbone. The receptor binding domain of such a protein can be transferred into another protein, for instance a therapeutically active one. This technique is commonly applied in the preparation of recombinant targeting constructs, and will be discussed in Section 11.8.2. 

RenaudJ. E, Rochel, N., Ruff, M., Vivat, V., Chambon, P, Gronemeyer, H. and Moras,D., Crystal structure of the RAR- hgand-binding domain bound to all-trans retinoic add (1995) Nature 378, 681-689... 

In many receptors, the extracellular domain contains the hgand binding site. Glycosy-lation sites, i.e., attachment sites for carbohydrate residues, are also located nearby in the extracellular domain. 

Receptor tyrosine kinases are integral membrane proteins that have a hgand-binding domain on the extracellular side and a tyrosine kinase domain on the cytosohc side (see Fig. 8.1). The transmembrane portion is made up of just one structural element thus it is assumed that it crosses the membrane in an a-hehcal form. On the cytoplasmic side, in addition to the conserved tyrosine kinase domain, there are also further regulatory sequence portions at which autophosphorylation, and phosphorylation and dephosphorylation by other protein kinases and by protein phosphatases, can take place. 

Ligand binding on the extracellular side is linked to stimulation of tyrosine kinase activity in the cytoplasmic receptor domain for receptors with intrinsic tyrosine kinase activity, the receptor tyrosine kinases (see 8.1). The hgand binding site and the tyrosine kinase are part of one and the same protein. 

The integrins do not have any enzyme activity in their own cytoplasmic domain, but on hgand binding, stimulation of tyrosine phosphorylation is observed on the cytoplasmic side of many cells, such as fibroblasts and platelets. The exact configuration of protein-protein interactions on the cytosolic side of the integrins is not clear and the mechanism of stimulation of protein tyrosine kinases is unknown. Some components of the focal adhesion points, such as the structural protein tensin, have SH2 and SH3 domains that may serve as specific attachment points for tyrosine kinases and other signal proteins. 

Bledsoe RK, Montana VG, Stanley TB, Delves CJ, Apohto CJ, McKee DD, Consler TG, Parks DJ, Stewart EL, Willson TM, Lambert MH, Moore JT, Pearce KH, Xu HE. Crystal structure of the glucocorticoid receptor hgand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 2002 110 93-105. 

Soderholm AA, Lehtovuori PT, Nyronen TH. Three-dimensional structure-activity relationships of nonsteroidal ligands in complex with androgen receptor hgand-binding domain. J Med Chem 2005 48 917-25. 

Figure 2.4 is a model of 17a-ruthenocenylethynyl-estradiol in the hgand binding domain of ERa [84,130]. 

PXR shares common stractural features that are characteristic of nuclear receptors [49] a DNA binding domain (DBD), hinge and hgand-bind-ing domain (LBD). Ligand-independent activation function 1 (AF-1) is shortened in PXR and... 

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