The largest group of biological targets for therapeutic intervention comprises the membrane proteins. These proteins perform various functions in the cell, serving as enzymes, pumps, channels, transporters, and receptors. To emphasize the importance of considering membrane proteins, ca. 40% of all drugs target G-protein-coupled receptors.
The first membrane structure was reported in 1985 of the photosynthetic reaction center from Rhodopseudomonas viridis. Today, the number of known membrane protein structures is still limited. Currently, the 3D structures are only known for 160 unique membrane protein structures including proteins of the same type from different organisms (Membrane Proteins of Known 3D Structure Web site, June 2008). The number of membrane protein structures and the change in the number of structures as a function of time are similar to the state of soluble protein structures approximately 25 years ago. The reason for this is primarily that expression, purification, and crystallization of membrane proteins are still nontrivial and require substantial time and resources. At the same time, structure determination of and biostructure-based drug design on membrane proteins represent one of the most challenging areas of modern drug research.
Another strategy taken on membrane proteins is to produce soluble constructs of parts of the proteins, e.g. the extracellular ligand-binding core of ionotropic glutamate receptors (iGluRs). These receptors mediate most fast excitatory synaptic transmission within the central nervous system (see Chapter 15). The glutamate receptors are not only involved in various aspects of normal brain functions but are also implicated in a variety of brain disorders and diseases. Hence, iGluRs are potential targets for biostructure-based drug design.
In 1998, the first structure of a ligand-binding core construct of an iGluR was reported, and presently ca. 90 structures of iGluRs with bound glutamate, agonists, antagonists, or allosteric modulators have been reported. The binding of ligands to the ligand-binding core of iGluRs can be described as a "Venus flytrap" mechanism. In the resting state the ligand-binding core is present in an open form and it is this form that is stabilized by competitive antagonists (Figures 2.11 and 2.12). When glutamate or an agonist binds to the ligand-binding core, a change in conformation occurs, resulting in a closed form of the ligand-binding core. In full-length receptors, this domain closure is thought to lead to the opening of the ion-channel (receptor activation). The presence of more than one conformation of the ligand-binding core of iGluRs clearly stresses the importance of knowing more than one structure of the receptor as fundament for biostructure-based drug design (for further details on glutamate receptor structures, see Sections 1.3.2 and 12.2.2, and Chapter 15).
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