6m38

X-ray structure of a Drosophila dopamine transporter with subsiteB mutations (D121G/S426M) in S-duloxetine bound form

spinqualitylabelsall models 6m38, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6m38 is a 3 chain structure with sequence from Drosophila melanogaster and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.001Å Ligands: 29E, CL, CLR, DMU, NA, Y01 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DAT_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). Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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