Paper Info
Title
Exploring Conformational Dynamics of the Extracellular Venus Flytrap Domain of the GABAB Receptor: a Path-Metadynamics Study.
Abstract
gamma-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 GABA(B) receptor (GABA(B)-R) is a heterodimeric class C G protein-coupled receptor (GPCR) comprised of GABA(B1a/b) and GABA(B2) subunits. The orthosteric binding site for GABA is located in the extracellular Venus flytrap (VFT) domain of the GABA(B1a/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 GABA(B1b)-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.
Year
DOI
Venue
2020
10.1021/acs.jcim.0c00163
JOURNAL OF CHEMICAL INFORMATION AND MODELING
DocType
Volume
Issue
Journal
60
4
ISSN
Citations 
PageRank 
1549-9596
0
0.34
References 
Authors
0
7
Name
Order
Citations
PageRank
Linn Mari Evenseth100.34
Riccardo Ocello200.34
Mari Gabrielsen330.74
Matteo Masetti423.45
Maurizio Recanatini5186.57
Ingebrigt Sylte683.35
Andrea Cavalli7102.82