A General Mechanism For Signal Propagation In The Nicotinic Acetylcholine Receptor Family
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY(2019)
摘要
Nicotinic acetylcholine receptors (nAChRs) modulate synaptic activity in the central nervous system. The alpha 7 subtype, in particular, has attracted considerable interest in drug discovery as a target for several conditions, including Alzheimer's disease and schizophrenia. Identifying agonist-induced structural changes underlying nAChR activation is fundamentally important for understanding biological function and rational drug design. Here, extensive equilibrium and nonequilibrium molecular dynamics simulations, enabled by cloud-based high-performance computing, reveal the molecular mechanism by which structural changes induced by agonist unbinding are transmitted within the human alpha 7 nAChR. The simulations reveal the sequence of coupled structural changes involved in driving conformational change responsible for biological function. Comparison with simulations of the alpha 4 beta 2 nAChR subtype identifies features of the dynamical architecture common to both receptors, suggesting a general structural mechanism for signal propagation in this important family of receptors.
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