TY - JOUR AU - Simon, Ágnes AU - Bencsura, Ákos AU - Héja, László AU - Magyar, Csaba AU - Kardos, Julianna TI - Sodium-Assisted Formation of Binding and Traverse Conformations of the Substrate in a Neurotransmitter Sodium Symporter Model. JF - CURRENT DRUG DISCOVERY TECHNOLOGIES J2 - CURR DRUG DISCOV TECHNOL VL - 11 PY - 2014 IS - 3 SP - 227 EP - 233 PG - 7 SN - 1570-1638 DO - 10.2174/1570163811666140812110735 UR - https://m2.mtmt.hu/api/publication/2765189 ID - 2765189 N1 - Institute of Cognitive Neuroscience and Psychology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, PO Box 17, H-1525, Budapest, Hungary Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary Institute of Enzimology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary Cited By :3 Export Date: 29 July 2021 Correspondence Address: Kardos, J.; Institute of Cognitive Neuroscience and Psychology, PO Box 17, H-1525, Hungary; email: kardos.julianna@ttk.mta.hu Chemicals/CAS: 4 aminobutyric acid, 28805-76-7, 56-12-2; sodium, 7440-23-5; carrier protein, 80700-39-6; GABA Plasma Membrane Transport Proteins; Membrane Transport Proteins; Neurotransmitter Agents; SLC6A1 protein, human; Sodium; Symporters AB - 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. LA - English DB - MTMT ER -