Fine architecture and mutation mapping of human brain inhibitory system ligand gated ion channels by high-throughput homology modeling

Abstract

The common architecture of the brain inhibitory system ligand-gated ion-channels was examined at the level of each of the subunits and in their assembled pentameric arrangements. Structural modeling of the GABAA receptor, GlyR1, and the serotonin receptor, 5HTR3A, was carried out on a multi-homolog basis employing a high-throughput homology modeling pipeline. The locations of all the known mutations of each of the subunits of the receptor subfamily were mapped upon their computed structures and structural relationships between patterns of mutations in different subunits were identified, resulting in the zoning of mutations to four specific regions of the common subunit structure. These classifications may be of value in discerning probable molecular mechanisms and functional manifestations of emerging mutations and polymorphisms, providing the foundation for a family-specific predictive algorithm that may allow researchers to focus experimental effort on the most probable molecular indicators of compromised receptor function and disease mechanism.