Article ID Journal Published Year Pages File Type
8648300 Journal of Structural Biology 2017 24 Pages PDF
Abstract
NMDA receptors are tetrameric ligand-gated ion channels that are crucial for neurodevelopment and higher order processes such as learning and memory, and have been implicated in numerous neurological disorders. The lack of a structure for the channel open state has greatly hampered the understanding of the normal gating process and mechanisms of disease-associated mutations. Here we report the structural modeling for the open state of an NMDA receptor. Staring from the crystal structure of the closed state, we repacked the pore-lining helices to generate an initial open model. This model was modified to ensure tight packing between subunits and then refined by a molecular dynamics simulation in explicit membrane. We identify Cα-H…O hydrogen bonds, between the Cα of a conserved glycine in one transmembrane helix and a carbonyl oxygen of a membrane-parallel helix, at the extracellular side of the transmembrane domain as important for stabilizing the open state. This observation explains why mutations of the glycine are associated with neurological diseases and lead to significant decrease in channel open probability.
Related Topics
Life Sciences Biochemistry, Genetics and Molecular Biology Molecular Biology
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