Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters

Pidathala, S and Mallela, AK and Joseph, D and Penmatsa, A (2021) Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters. In: Nature Communications, 12 (1).

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Abstract

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. © 2021, The Author(s).

Item Type:	Journal Article
Publication:	Nature Communications
Publisher:	Nature Research
Additional Information:	The copyright for this article belongs to Authors
Keywords:	Drosophila melanogaster
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	16 Jul 2021 06:06
Last Modified:	16 Jul 2021 06:06
URI:	http://eprints.iisc.ac.in/id/eprint/68762

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