Abstract
BackgroundThe mammalian neurotransmitter transporters are complex proteins playing a central role in synaptic transmission between neurons by rapid reuptake of neurotransmitters. The proteins which transport dopamine, noradrenaline and serotonin belong to the Neurotransmitter:Sodium Symporters (NSS). Due to their important role, dysfunctions are associated with several psychiatric and neurological diseases and they also serve as targets for a wide range of therapeutic and illicit drugs. Despite the central physiological and pharmacological importance, direct evidence on structure–function relationships on mammalian NSS proteins has so far been unsuccessful. The crystal structure of the bacterial NSS protein, LeuT, has been a turning point in structural investigations. Scope of reviewTo provide an update on what is known about the binding sites for substrates and inhibitors in the LeuT. The different binding modes and binding sites will be discussed with special emphasis on the possible existence of a second substrate binding site. It is the goal to give an insight into how investigations on ligand binding in LeuT have provided basic knowledge about transporter conformations and translocation mechanism which can pave the road for a deeper understanding of drug binding and function of the mammalian transporters. Major conclusionsThe LeuT is a suitable model for the structural investigation of NSS proteins including the possible location of drug binding sites. It is still debated whether the LeuT is a suitable model for the molecular mechanisms behind substrate translocation. General significanceStructure and functional aspects of NSS proteins are central for understanding synaptic transmission. With the purification and crystallization of LeuT as well as the dopamine transporter from Drosophila melanogaster, the application of biophysical methods such as fluorescence spectroscopy, neutron- or x-ray scattering and NMR for understanding its function becomes increasingly available. This article is part of a Special Issue entitled Structural biochemistry and biophysics of membrane proteins.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
More From: Biochimica et Biophysica Acta (BBA) - General Subjects
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.