6m47
From Proteopedia
X-ray structure of a Drosophila dopamine transporter with NET-like mutations (D121G/S426M/F471L) in tramadol bound form
Structural highlights
FunctionDAT_DROME Sodium-dependent dopamine transporter which terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals (PubMed:11125028, PubMed:12606774, PubMed:24037379, PubMed:25970245). Also transports tyramine and norepinephrine, shows less efficient transport of octopamine and does not transport serotonin (PubMed:11125028, PubMed:12606774). Plays a role in the regulation of the rest/activity cycle (PubMed:16093388, PubMed:25232310).[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedNorepinephrine 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. Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters.,Pidathala S, Mallela AK, Joseph D, Penmatsa A Nat Commun. 2021 Apr 13;12(1):2199. doi: 10.1038/s41467-021-22385-9. PMID:33850134[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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