The type A gamma-aminobutyric acid (GABA_A) receptor plays a major inhibitory role in the central nervous system. Its functions are allosterically regulated by several therapeutic compounds, such as benzodiazepines. Although these drugs are very potent and efficient, they also have many side effects. In order to develop better drugs targeting this receptor, the detailed three-dimensional structure of GABA_A receptor is needed to be determined. However, GABA_A receptor is a large polymeric transmembrane protein, which presents formidable problems to current structural biology techniques . Hence, an over-expressed 131-residue extracellular membrane-proximal fragment of GABA_A receptor αl subunit, Cys166-Leu296, which harbors most of the important ligand-binding sites, was chosen to study. Tec...[ Read more ]

The type A gamma-aminobutyric acid (GABA_A) receptor plays a major inhibitory role in the central nervous system. Its functions are allosterically regulated by several therapeutic compounds, such as benzodiazepines. Although these drugs are very potent and efficient, they also have many side effects. In order to develop better drugs targeting this receptor, the detailed three-dimensional structure of GABA_A receptor is needed to be determined. However, GABA_A receptor is a large polymeric transmembrane protein, which presents formidable problems to current structural biology techniques . Hence, an over-expressed 131-residue extracellular membrane-proximal fragment of GABA_A receptor αl subunit, Cys166-Leu296, which harbors most of the important ligand-binding sites, was chosen to study. Techniques such as computer structural prediction, transmission electron microscopy, circular dichroism in various detergent solutions, X-ray crystallization, laser scattering and nuclear magnetic resonance was used to characterize the secondary, tertiary and quaternary structure as well as the physical behaviors of this pharmacological interested fragment.