Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters
| Autor: | Shabareesh Pidathala, Deepthi Joseph, Aditya Kumar Mallela, Aravind Penmatsa |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Models Molecular Neurotransmitter transporter Science Dopamine General Physics and Astronomy Pharmacology Crystallography X-Ray General Biochemistry Genetics and Molecular Biology Article Norepinephrine uptake Norepinephrine (medication) Norepinephrine 03 medical and health sciences 0302 clinical medicine Neurotransmitter Transport Proteins Sf9 Cells medicine Animals Drosophila Proteins Humans Transporters in the nervous system X-ray crystallography 030304 developmental biology Dopamine transporter Mice Knockout Dopamine Plasma Membrane Transport Proteins 0303 health sciences Multidisciplinary Binding Sites biology Chemistry General Chemistry 3. Good health Analgesics Opioid 030104 developmental biology Drosophila melanogaster HEK293 Cells Norepinephrine transporter biology.protein Catecholamine Transcriptome Reuptake inhibitor 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | 'Nature Communications ', vol: 12, pages: 2199-1-2199-12 (2021) Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021) |
| ISSN: | 2041-1723 |
| Popis: | Norepinephrine is a biogenic amine neurotransmitter that has widespread effects on alertness, arousal and pain sensation. Consequently, blockers of norepinephrine uptake have served as vital tools to treat depression and chronic pain. Here, we employ the Drosophila melanogaster dopamine transporter as a surrogate for the norepinephrine transporter and determine X-ray structures of the transporter in its substrate-free and norepinephrine-bound forms. We also report structures of the transporter in complex with inhibitors of chronic pain including duloxetine, milnacipran and a synthetic opioid, tramadol. When compared to dopamine, we observe that norepinephrine binds in a different pose, in the vicinity of subsite C within the primary binding site. Our experiments reveal that this region is the binding site for chronic pain inhibitors and a determinant for norepinephrine-specific reuptake inhibition, thereby providing a paradigm for the design of specific inhibitors for catecholamine neurotransmitter transporters. The Drosophila dopamine transporter (dDAT) is a catecholamine neurotransmitter transporter that resembles the human norepinephrine transporter (hNET). Here the authors report X-ray structures of the dDAT in substrate-free form, norepinephrine-bound form and dDAT bound to commonly prescribed chronic pain inhibitors duloxetine, milnacipran and tramadol and shed light on the structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters. |
| Databáze: | OpenAIRE |
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