Bridging structural biology and genetics by computational methods: An investigation into how the R774C mutation in the AR gene can result in complete androgen insensitivity syndrome

Publisher Website
Google Scholar
Abstract
Recent structural studies of the ligand-binding domain (LBD) of the androgen receptor (AR) have raised more questions than answers, as most of the known pathogenic mutations of the AR gene causing androgen insensitivity syndrome (AIS) are not in the ligand-binding pocket. In this study, we have investigated one such pathogenic mutation, by examining details of its altered atomic structure using a computational technique of molecular dynamics (MD) simulations extended over 4 ns, effectively creating a 4D structural model. The mutation R774C, which is in the LBD of the AR gene, causes complete AIS (CAIS), producing ARs that have a unique thermolabile profile, being thermostable at 22°C but thermolabile at 37°C. We have therefore investigated this mutation by MD simulations at 293 K (20°C), 300 K (27°C), and 310 K (37°C). The MD simulations indicate that: 1) the mutation causes local structural distortions, which result in changes in the shape of the ligand-binding pocket; 2) the mutation alters the dynamic nature of the protein and results in a more diverse conformational distribution of the ligand-binding pocket; and 3) the effect of the mutation on AR structure could be largely reversed by lowering the temperature at which the MD simulations were conducted. These results therefore strongly support the biochemical data, e.g., the mutants' inability to form AR-ligand complexes at 37°C and its characteristic reversible thermolability, clearly indicating the value of such computational methods. Hum Mutat 22:465–475, 2003.