Growth factor receptors: Structure, mechanism, and drug discovery

The focus of this review is the relationship between the three-dimensional structure of ligands of the various members of the growth factor receptor tyrosine kinase superfamily and their interaction with the cognate receptor. Particular attention is given to the transforming growth factor-alpha, epidermal growth factor (EGF); nerve growth factor, neurotrophin; and insulin-like growth factor-1 (IGF-1), insulin systems since these have been extensively studied in recent years. The three receptor types, which bind these ligands, are the epidermal growth factor receptor family (erb B receptors), the neurotrophin or Trk receptor family, and IGF-1/insulin receptors, respectively, and represent three distinct members of the tyrosine kinase superfamily. For each of these, formation of the ligand-receptor complex initiates the signal transduction cascade through autophosphorylation by the intracellular tyrosine kinase domain. The extracellular portion of the receptor that contains the ligand binding domain in these systems varies significantly in organization in each case. For the EGF receptor system, ligand binding induces homo- and heterodimerization of the receptor leading to activation of the intracellular kinase. For the Trk receptor system, homodimerization of receptors has been shown to occur, although a second receptor, p75, is also required for high affinity binding of neurotrophins and for enhanced sensitivity of tyrosine kinase activation at low ligand concentrations. The IGF-1 and insulin receptors exist as covalent cross-linked dimers where each monomer is composed of two subunits. The aim of this review is also to discuss the mechanism of ligand-receptor interaction for each of these cases; however, since no structural information is yet available for the ligand-receptor complex, the discussion will largely be centered on the molecular requirements of ligand binding. As these receptors are activated through the ligand binding site on the extracellular domain, this represents a possible target for pharmacological intervention by inhibition or stimulation of this portion of the receptor. Thus from a drug design perspective, the focus of this review is to discuss progress in the development of agonists or antagonists of the ligand for these receptors.