Ligand Binding and Activation

The tyrosine kinase activity localized on the cytosohc side of the receptor is stimulated by extracellular hgand binding. Activation by extracellular hgands is based on a ligand-mediated change of oligomer status of the receptor. Stimulation of the tyrosine kinase activity can have a two-fold effect Firstly, an autophosphorylation of the receptor may take place in trans, i.e., between different protomers of the receptor (Fig. 8.3). Secondly, substrate proteins may be phosphorylated on Tyr residues. 

The ligands of the receptor tyrosine kinases are generally multivalent. The multiple binding sites of the ligand enable it to orient two (or more) of the receptor subimits so that their cytosolic tyrosine kinase activity is stimulated. 

In some cases, the ligand itself has a dimeric structure and induces formation of active receptor dimers on binding to the receptor. One example is PDGF, which exists as a disulfide bridge-linked dimeric protein. 

An aspect of ligand-induced oligomerization of receptors of regulatory importance is the possibility to form heterodimers. Protein families composed of closely related members can be identified for a number of growth factors and corresponding receptors. 

Analogous to heterotypical dimerization of transcription factors (see Chapter 1.2), heterologous dimerization is observed within different members of a receptor family. A certain growth hormone can thus bind to and activate different dimeric combinations of the members of a receptor family. Fig. 8.5. shows the possibilities for heterodimerization of receptors, using the PDGF receptor as an example (review Lemmon and Schlessinger, 1994). 

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Analysis of the opening and closing events of individual channels has provided information about ligand binding and activation of the receptor 201... 

Sabey K, Paradiso K, Zhang J, Steinbach JH (1999) Ligand binding and activation of rat nicotinic a4 32 receptors stably expressed in HEK293 cells. Mol Pharmacol 55 58-66... 

The identification and characterization of the processes of GPCR activation and inactivation have defined the genomics of the accessory proteins necessary to these processes. This has accelerated progress in understanding the fundamental mechanisms involved in GPCR synthesis, transport to the membrane, ligand binding, and activation and inactivation by GRK-mediated (and other) phosphorylation (192). 

E. The /32AR as a Model System for Ligand Binding and Activation ... 

FIGURE 5.5 There are five isoforms of SIP receptors (SlPn 5), a family of G protein-coupled membrane receptors previously known as Edg receptors (endothelial differentiation gene). Ligand binding and activation of SIP receptors initiates multiple intracellular signaling cascades involved in cellular proliferation, differentiation, survival and migration. 

Seven-Transmembrane-Helix Receptors Change Conformation in Response to Ligand Binding and Activate G Proteins... 

Feng W, Song ZH (2003) Effects of D3.49A, R3.50A, and A6.34E mutations on ligand binding and activation of the cannabinoid-2 (CB2) receptor. Biochem Pharmacol 65 1077-1085... 

E.P. Baldwin, and L. Bonati (2002). Ligand binding and activation of the Ah receptor. Chem. Biol. Interact. 141, 3-24. 

X. Ding, X. Zhao and A. Watts, G-Protein-Coupled Receptor Structure, Ligand Binding and Activation as Studied by Solid-State NMR Spectroscopy, Biochem. /., 2013, 450, 443. 

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