Homology Modelling of the GABA Transporter and Analysis of Tiagabine Binding

• DOI: 10.1002/cmdc.201000100
• Publication Date: 2010-05-24T11:13:06Z
• Authors: Søren Skovstrup; Olivier Taboureau; Hans Bräuner‐Osborne; Flemming Steen Jø...
• Keywords: Tiagabine; Nipecotic acid; GABA transporter; Docking (animal)

A homology model of the human GABA transporter (GAT-1) based on recently reported crystal structures bacterial leucine from Aquifex aeolicus (LeuT) was developed. The stability resulting embedded in a membrane environment analyzed by extensive molecular dynamics (MD) simulations. Based docking studies and subsequent MD simulations three compounds, endogenous ligand two potent inhibitors, (R)-nipecotic acid anti-epilepsy drug tiagabine, various binding modes were identified are discussed. Whereas acid, which both substrates, stabilised with residues located deep inside occluded state pocket (including Tyr 60 Ser 396), contains large aliphatic side chain, is mode that extends substrate (i.e., Phe 294) to extracellular vestibule, where chain residues. tiagabine mode, reaching site forces 294 adopt distinct conformation found transporter. Hence, presence GAT-1 constrained an open-to-out conformation. Our results may be particular interest for design new inhibitors.