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Download fileExploring Conformational Dynamics of the Extracellular Venus flytrap Domain of the GABAB Receptor: A Path-Metadynamics Study
journal contribution
posted on 2020-04-15, 13:03 authored by Linn S. M. Evenseth, Riccardo Ocello, Mari Gabrielsen, Matteo Masetti, Maurizio Recanatini, Ingebrigt Sylte, Andrea Cavalliγ-Aminobutyric
acid (GABA) is the main inhibitory neurotransmitter
in the central nervous system (CNS). Dysfunctional GABAergic neurotransmission
is associated with numerous neurological and neuropsychiatric disorders.
The GABAB receptor (GABAB-R) is a heterodimeric
class C G protein-coupled receptor (GPCR) comprised of GABAB1a/b and GABAB2 subunits. The orthosteric binding site for
GABA is located in the extracellular Venus flytrap (VFT) domain of the GABAB1a/b. Knowledge about molecular
mechanisms and druggable receptor conformations associated with activation
is highly important to understand the receptor function and for rational
drug design. Currently, the conformational changes of the receptor
upon activation are not well described. On the basis of other class
C members, the VFT is proposed to fluctuate between an open/inactive
and closed/active state and one of these conformations is stabilized
upon ligand binding. In the present study, we investigated the dynamics
of the GABAB1b-R VFT in the apo form by combining unbiased
molecular dynamics with path-metadynamics. Our simulations confirmed
the open/inactive and closed/active state as the main conformations
adopted by the receptor. Sizeable energy barriers were found between
stable minima, suggesting a relatively slow interconversion. Previously
undisclosed metastable states were also identified, which might hold
potential for future drug discovery efforts.
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GABA B 1aGABA B 1bExploring Conformational DynamicsPath-Metadynamics Study γ- Aminobut...Extracellular Venus flytrap Domainreceptor functionR VFTligand bindingfuture drug discovery effortsGABA B 2 subunitsGABA Bmetastable statesSizeable energy barriersGABA B receptorDysfunctional GABAergic neurotransm...GABA B Receptororthosteric binding sitedrug designclass C membersheterodimeric class C G protein-cou...extracellular Venus flytrapapo formGPCRCNSdruggable receptor conformations