B2-Receptors Extracellular Cell membrane Receptor Ho. 1 the receptor and has a binding site waiting to receive its chemical messenger.The intracellular region acts as a tyrosine kinase enzyme and has an active site, is closed when the receptor is in the resting stal The reaction catalyzed by this enzyme is the phosphorylation of tyrosine residues in protein substrates(Fig. 12). In order to carry out the reaction, adeno- sine triphosphate (ATP)is required to supply the phosphate unit. aTP is itself dephosphorylated to adenosine diphosphate(Adp)(Fig. 13) hormones, such as insulin, growth factors and cytokines. To illustrate what appens when a tyrosine kinase-linked receptor is activated, we shall look at a ADP e⊙d Tyrosine Fg. 13. Dephosphorylation of ATP
Section B- Drug targets specific example- the epidermal growth factor receptor (EGF-R), so called because the chemical messenger is the hormone epidermal growth factor(EGF) ( ig. 14). Epidermal growth factor is a protein that can act as a bivalent ligand This means that one molecule can bind to two separate receptors resulting in receptor dimerization. Both receptors in the dimer change shape and this opens up the kinase active site in each receptor. The kinase enzyme of each half of the dimer can then catalyze the phosphorylation of tyrosine residues in protein substrates. Since the most accessible protein is the other half of the dimer, each enzyme catalyzes phosphorylation of the tyrosine residues of its Phosphorylation of the EGF-R dimer initiates a rather complex cascade effect which begins with the binding of various proteins and enzymes to the phos- phorylated regions. Some of these proteins act as signal proteins, which are activated and travel to other parts of the cell in order to initiate further processes. Others are enzymes, which are activated to catalyze further reactions within the cell. The full story of this process is too complex to be included in a text of this sort. Suffice it to say that the end effect is the activation of proteins called transcription proteins, which interact with DNA and initiate gene expression. This switches on the synthesis of cell proteins, resulting in cell wth and cell division It has been observed that several cancers are associ- ated with the unregulated activity of kinase receptors such as the EGF receptor Therefore, the design of compounds that switch off the tyrosine kinase activity f such receptors may be of interest in fighting cancer. A case study on this topic is given in Section L EGF Phosphorylation Closed TP P=phosphate groups Signal Fig. 14. Activation of the epidermal growth factor receptor. intracellular lot all receptors are membrane bound. There are a group of receptors that exist within the cell which interact with chemical messengers such as steroids, thyroid hormones and retinoids. The chemical messengers involved have to be suffi- ciently hydrophobic in order to cross the cell membrane to reach their target receptors. The estrogen receptor is an example of an intracellular receptor, which exists in the cytoplasm as a complex with another protein(Fig. 15).When the female hormone estrogen enters the cell, it binds to the receptor-protein complex resulting in dissociation of the protein-receptor complex. The receptor-ligand complex then enters the nucleus and binds to specific dNA sequences, thus activating transcription and the generation of mRNA, which is then translated to form various functional and structural protein
B2-Receptors Translatio 叫 complex Fig. 15. Activation of the estrogen receptor(ER)
Section B-Drug targets B3 CARRIER PROTEINS Key Notes Carrier proteins transport important polar molecules across the cell membrane. They do so by enclosing the polar molecule in a hydrophil Carrier protein Carrier protein blockers are drugs that either bind to a carrier protein and blockers prevent it from accepting its natural guest, or compete with the natural guest for transport into the cell. Drugs such as the tricyclic antidepressants, cocaine and amphetamine hinder the uptake of important neurotransmitters from nerve synapses, resulting in increased Some polar drugs can be'smuggled across cell ranes by carrier proteins if the drug is attached to a natural guest molecule Related topics Drug absorption(C2) Drug distribution( C3) Function Carrier proteins float freely through cell membranesvisiting' the outer and inner surfaces of the membrane (Fig. 1).They have an outer surface of hydrophobic amino acids, which can interact with the fatty cell membrane by van der Waals interactions. In the center, there is a hydrophilic cavity, whic can accommodate polar molecule The function of a carrier protein is to 'smuggle important polar molecules cross the cell membrane It ar molecule inside the hydrophilic cavity, transporting the concealed molecule across the membrane, then releasing it into the cell. Carrier proteins are crucial in trans- porting many of the building blocks required for the cell's survival. For example there are carrier proteins that are specific for the transport of the amino acid building blocks required for protein synthesis. Other carrier proteins are used to transport the nucleic acid bases required for nucleic acid synthesis. Polar o guest Memb 1. Function of camier proteins
B3-Carrier proteins Without carrier proteins, these polar molecules would not be able to cross the ydrophobic cell membrane the synthesis of proteins and nucleic acids would ease and the cell would die. Carrier proteins are also important in transporting mportant neurotransmitters such as ne brine and dopamine back into the nerves from which they were released Carrer protein Some drugs prevent carrier proteins transporting their natural guest (Fig. 2).For blockers example, the tricyclic antidepressants work by inhibiting the uptake of norepi nephrine by its carrier protein. These carrier proteins are responsible for trans- rine from the synaptic gap back into th from which it was released. Inhibition of this process means that the released norepinephrine remains in the synapse for a longer period of time and reactivates the adrenergic receptors of the target cell. As a result, adrenergic activity increases. Cocaine acts iting the carrier proteins for norepinephrine in the peripheral nervous system as well as the carrier proteins for dopamine in the central nervous systen The former activity is responsible for the physical effects of cocaine(e.g. suppres- sion of hunger), while the latter is responsible for the psychological effects (e.g Some drugs compete with the natural guest for its carrier protein.For example, amphetamine is transported into nerves by the carrier protein for orepinephrine. This means that it takes the carrier protein longer to transport norepinephrine back into the nerve, resulting in greater receptor activation and Nerve Nerve Release of Carrier neurotransmitter Receptor activation a d-Blocker Uptake blocked Increased transmission Fg. 2. Carrier protein blockade