Journal
STRUCTURE
Volume 27, Issue 7, Pages 1171-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2019.04.008
Keywords
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Funding
- EPSRC [EP/N024117/1]
- UK Collaborative Computational Project on Biomolecular Simulation [EP/M022609/1]
- EPSRC [EP/G007705/1, EP/N024117/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/G007705/1] Funding Source: researchfish
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Nicotinic acetylcholine receptors (nAChRs) modulate synaptic transmission in the nervous system. These receptors have emerged as therapeutic targets in drug discovery for treating several conditions, including Alzheimer's disease, pain, and nicotine addiction. In this in silico study, we use a combination of equilibrium and nonequilibrium molecular dynamics simulations to map dynamic and structural changes induced by nicotine in the human alpha 4 beta 2 nAChR. They reveal a striking pattern of communication between the extracellular binding pockets and the transmembrane domains (TMDs) and show the sequence of conformational changes associated with the initial steps in this process. We propose a general mechanism for signal transduction for Cysloop receptors: the mechanistic steps for communication proceed firstly through loop C in the principal subunit, and are subsequently transmitted, gradually and cumulatively, to loop F of the complementary subunit, and then to the TMDs through the M2-M3 linker.
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