6M0Z

X-ray structure of Drosophila dopamine transporter with NET-like mutations (D121G/S426M/F471L) in L-norepinephrine bound form

Summary for 6M0Z

• Entry DOI: 10.2210/pdb6m0z/pdb
• Related: 6M0F
• Descriptor: Sodium-dependent dopamine transporter, Antibody fragment (Fab) 9D5 Light chain, Antibody fragment (Fab) 9D5 heavy chain, ... (10 entities in total)
• Functional Keywords: neurotransmitter transporter, antibody fragment, membrane protein
• Biological source: Drosophila melanogaster (Fruit fly); More
• Total number of polymer chains: 3
• Total formula weight: 108633.17

Authors

Shabareesh, P.,Mallela, A.K.,Joseph, D.,Penmatsa, A. (deposition date: 2020-02-24, release date: 2021-02-17, Last modification date: 2024-11-06)

Primary citation

Pidathala, S.,Mallela, A.K.,Joseph, D.,Penmatsa, A.
Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters.
Nat Commun, 12:2199-2199, 2021

PubMed 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.

PubMed: 33850134
DOI: 10.1038/s41467-021-22385-9

Experimental method

X-RAY DIFFRACTION (2.88 Å)