Putative drug binding conformations of monoamine transporters
Autor: | Svein G. Dahl, Kurt Kristiansen, Ingebrigt Sylte, Aina Westrheim Ravna |
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Rok vydání: | 2006 |
Předmět: |
Models
Molecular Lactose permease Protein Conformation Molecular Sequence Data Clinical Biochemistry Pharmaceutical Science Citalopram In Vitro Techniques Ligands Biochemistry Protein structure Cocaine Drug Discovery Humans Biogenic Monoamines Amino Acid Sequence Homology modeling Molecular Biology Serotonin transporter Dopamine transporter Serotonin Plasma Membrane Transport Proteins Dopamine Plasma Membrane Transport Proteins Binding Sites Norepinephrine Plasma Membrane Transport Proteins Sequence Homology Amino Acid Symporters biology Chemistry Permease Organic Chemistry Major facilitator superfamily Amphetamine Monoamine neurotransmitter biology.protein Thermodynamics Molecular Medicine Selective Serotonin Reuptake Inhibitors |
Zdroj: | Bioorganic & Medicinal Chemistry. 14:666-675 |
ISSN: | 0968-0896 |
Popis: | Structural information about monoamine transporters and their interactions with psychotropic drugs is important for understanding their molecular mechanisms of action and for drug development. The crystal structure of a Major Facilitator Superfamily (MFS) transporter, the lactose permease symporter (lac permease), has provided insight into the three-dimensional structure and mechanisms of secondary transporters. Based on the hypothesis that the 12 transmembrane alpha-helix (TMH) secondary transporters belong to a common folding class, the lac permease structure was used for molecular modeling of the serotonin transporter (SERT), the dopamine transporter (DAT), and the noradrenaline transporter (NET). The molecular modeling methods used included amino acid sequence alignment, homology modeling, and molecular mechanical energy calculations. The lac permease crystal structure has an inward-facing conformation, and construction of outward-facing SERT, DAT, and NET conformations allowing ligand binding was the most challenging step of the modeling procedure. The psychomotor stimulants cocaine and S-amphetamine, and the selective serotonin reuptake inhibitor (SSRI) S-citalopram, were docked into putative binding sites on the transporters to examine their molecular binding mechanisms. In the inward-facing conformation of SERT the translocation pore was closed towards the extracellular side by hydrophobic interactions between the conserved amino acids Phe105, Pro106, Phe117, and Ala372. An unconserved amino acid, Asp499 in TMH10 in NET, may contribute to the low affinity of S-citalopram to NET. |
Databáze: | OpenAIRE |
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