Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-22385-9
Keywords
-
Categories
Funding
- Department of Science and Technology, India [DSTO-1668]
- ESRF access program of the RCB of the Department of Biotechnology, India [BT/INF/22/SP22660/2017]
- Wellcome Trust/DBT India Alliance Intermediate Fellowship [IA/1/15/2/502063]
- DBT-IYBA [BT/09/IYBA/2015/13]
- DBT-RA program in Biotechnology and Life Sciences
- DST-INSPIRE fellowship [IF160278]
- DBT-IISc partnership program
- DST-FIST
- IISc-Institute of Eminence program
- Department of Science and Technology-Science and Engineering Research Board (DST-SERB) [IR/SO/LU/0003/2010-PHASE-II]
- EMBO Global Investigator from India
Ask authors/readers for more resources
The researchers used the Drosophila melanogaster dopamine transporter as a surrogate to study the structure and function of norepinephrine, revealing potential paradigms for designing chronic pain inhibitors.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available