Abstract
γ-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.
Highlights
ABSTRACT: γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system (CNS)
Each subunit consists of an extracellular Venus flytrap (VFT) linked to a heptahelical transmembrane (7TM) domain (Figure 1),[5] and GABAB-R does not contain the cysteine-rich linker that has been shown to play an important role in transmitting the activation signal from the VFT to the 7TM of other class C G protein-coupled receptor (GPCR).[5]
The results showed that the Cα root mean square deviation (RMSD) from the unbiased molecular dynamics (MD) simulations of GABAB1b VFT in the closed/active state (PDB IDs: 4MS3 and 4MS4) diverged at the beginning of the simulation, but afterward their RMSDs reached similar values, indicating an overlapping conformational space for the rest of the simulation (Figure S4, green plots)
Summary
ABSTRACT: γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system (CNS). The receptor belongs to class C of G-protein coupled receptors (GPCRs), together with the metabotropic glutamate receptors (mGlu1-8-R), the calcium-(CaSR), and sweet and umami taste receptors.[5] Each subunit consists of an extracellular Venus flytrap (VFT) linked to a heptahelical transmembrane (7TM) domain (Figure 1),[5] and GABAB-R does not contain the cysteine-rich linker that has been shown to play an important role in transmitting the activation signal from the VFT to the 7TM of other class C GPCRs.[5] Likewise, the disulfide bridge that cross-links the VFT dimer of mGluRs is not present in the GABAB-R VFT.[5]. Binding studies with recombinant receptor mutants, radioligand binding, and displacement assays have shown that the VFT of GABAB1a/b VFT, with is functional in reduced agonist absence of the affinities.[6,10−12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
