TY - JOUR
T1 - Identification of the Initial Steps in Signal Transduction in the α4β2 Nicotinic Receptor: Insights from Equilibrium and Nonequilibrium Simulations
AU - Oliviera, Sofia
AU - Shoemark, Deborah K.
AU - Rego Campello, Hugo
AU - Wonnacott, Susan
AU - Gallagher, Tim
AU - Sessions, Richard B.
AU - Mulholland, Adrian J.
PY - 2019/7/2
Y1 - 2019/7/2
N2 - 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 α4β2 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 Cys-loop 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.
AB - 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 α4β2 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 Cys-loop 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.
KW - Cys-loop receptor
KW - MD simulations
KW - conformational changes
KW - nicotine binding
KW - nicotinic receptor
UR - https://doi.org/10.1016/j.str.2019.04.008
UR - http://www.scopus.com/inward/record.url?scp=85067867093&partnerID=8YFLogxK
U2 - 10.1016/j.str.2019.04.008
DO - 10.1016/j.str.2019.04.008
M3 - Article
SN - 0969-2126
VL - 27
SP - 1171-1183.e3
JO - Structure
JF - Structure
IS - 7
ER -