Sodium-Assisted Formation of Binding and Traverse Conformations of the Substrate in a Neurotransmitter Sodium Symporter Model.

Simon, Á [Simon, Ágnes (Fehérjék számítóg...), szerző] Kognitív Idegtudományi és Pszichológiai Intézet (MTA TTK); Bencsura, Á [Bencsura, Ákos (Reakciókinetika), szerző] Szerves Kémiai Intézet (MTA TTK); Héja, L [Héja, László (Neurokémia), szerző] Kognitív Idegtudományi és Pszichológiai Intézet (MTA TTK); Magyar, C [Magyar, Csaba (Fehérjék szerkeze...), szerző] Enzimológiai Intézet (MTA TTK); Kardos, J [Kardos, Julianna (Neurokémia, az id...), szerző] Szerves Kémiai Intézet (MTA TTK)

Angol nyelvű Tudományos Szakcikk (Folyóiratcikk)
Megjelent: CURRENT DRUG DISCOVERY TECHNOLOGIES 1570-1638 11 (3) pp. 227-233 2014
  • SJR Scopus - Drug Discovery: Q2
Azonosítók
Szakterületek:
    Therapeutics designed to increase synaptic neurotransmitter levels by inhibiting neurotransmitter sodium symporters (NSSs) classify a strategic approach to treat brain disorders such as depression or epilepsy, however, the critical elementary steps that couple downhill flux of sodium to uphill transport of neurotransmitter are not distinguished as yet. Here we present modelling of NSS member neuronal GAT1 with the substrate gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter. GABA binding is simulated with the occluded conformation of GAT1 homodimer in an explicit lipid/water environment. Simulations performed in the 1-10 ns range of time elucidated persistent formation of half-extended minor and H-bridged major GABA conformations, referred to as binding and traverse conformations, respectively. The traverse GABA conformation was further stabilized by GAT1-bound Na+(1). We also observed Na+(1) translocation to GAT1-bound Cl- as well as the appearance of water molecules at GABA and GAT1-bound Na+(2), conjecturing causality. Scaling dynamics suggest that the traverse GABA conformation may be valid for developing substrate inhibitors with high efficacy. The potential for this finding is significant with impact not only in pharmacology but wherever understanding of the mechanism of neurotransmitter uptake is valuable.
    Hivatkozás stílusok: IEEEACMAPAChicagoHarvardCSLMásolásNyomtatás
    2020-07-07 07:55