Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Unveiling conformation-selective regulation of the norepinephrine transporter.
Journal, issue, pages	Cell, Vol. 188, Issue 24, Page 6861-6872.e14, Year 2025
Publish date	Nov 26, 2025
Authors	Heng Zhang / Tianwei Zhang / Dingyan Wang / Antao Dai / Jianhang Mao / Qihui Chen / Tianyuan Du / Xue Lu / Yongxin Hao / Chao Zhang / Yu-Ling Yin / Wen Hu / Benxun Pan / Sanshan Jin / Mengting Jiang / Yuan Si / Qingning Yuan / Ming-Wei Wang / Mingyue Zheng / Zhen Wang / Dehua Yang / H Eric Xu / Yi Jiang /
PubMed Abstract	The norepinephrine transporter (NET) plays a crucial role in synaptic neurotransmission and is implicated in major depression and attention-deficit/hyperactivity disorders, yet our understanding of ...The norepinephrine transporter (NET) plays a crucial role in synaptic neurotransmission and is implicated in major depression and attention-deficit/hyperactivity disorders, yet our understanding of its allosteric, conformation-selective regulation-crucial for developing targeted therapeutics-remains limited. Through cryo-electron microscopy analysis of NET complexes with levomilnacipran, vanoxerine, and vilazodone, we identify a previously undefined allosteric site within NET's inner vestibule that enables conformation-selective regulation. This discovery introduces a "valve model," in which specific residues partition the cytoplasmic cavity into distinct chambers, determining inhibitor binding specificity. Leveraging this structural insight through virtual screening, we identify a set of inhibitors with potent NET inhibitory activity and demonstrate their antidepressant effects. Moreover, our structural identification of inhibitor occupancy at this conformation-selective site defines a mechanistic framework for targeted therapeutic intervention. These findings advance our understanding of NET allosteric modulation, providing a structure-guided framework for developing next-generation antidepressants targeting the inward-open conformation of NET for the treatment of neuropsychiatric disorders.
External links	Cell / PubMed:41138730
Methods	EM (single particle)
Resolution	2.44 - 3.13 Å
Structure data	62267 9kda EMDB-62267, PDB-9kda: Cryo-EM structure of lipid-mediated dimer of human norepinephrine transporter NET in the presence of the antidepressant vilazodone in an inward-open state at resolution of 2.44 angstrom. Method: EM (single particle) / Resolution: 2.44 Å 62276 9kdh EMDB-62276, PDB-9kdh: Cryo-EM structure of LIPID-mediated dimer of human norepinephrine transporter NET in the presence of Vanoxerine in an inward-open state at resolution of 2.52 angstrom Method: EM (single particle) / Resolution: 2.52 Å 62281 9kdm EMDB-62281, PDB-9kdm: Cryo-EM structure of LIPID-mediated human norepinephrine transporter NET in the presence of Levomilnacipran in an inward-open state at resolution of 2.46 angstrom. Method: EM (single particle) / Resolution: 2.46 Å 62289 9ke3 EMDB-62289, PDB-9ke3: Cryo-EM structure of lipid-mediated dimer of human norepinephrine transporter NET in the presence of the F3288-0031 in an inward-open state at resolution of 3.1 angstrom Method: EM (single particle) / Resolution: 3.13 Å
Chemicals	ChemComp-YG7: 5-{4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl}-1-benzofuran-2-carboxamide ChemComp-CLR: CHOLESTEROL PDB-1efm: STRUCTURE OF THE GDP DOMAIN OF EF-TU AND LOCATION OF THE AMINO ACIDS HOMOLOGOUS TO RAS ONCOGENE PROTEINS ChemComp-HOH: WATER PDB-1d5s: CRYSTAL STRUCTURE OF CLEAVED ANTITRYPSIN POLYMER ChemComp-F0F: (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-cyclopropane-1-carboxamide PDB-1efr: BOVINE MITOCHONDRIAL F1-ATPASE COMPLEXED WITH THE PEPTIDE ANTIBIOTIC EFRAPEPTIN
Source	homo sapiens (human)
Keywords	PROTON TRANSPORT / Complex / TRANSPORT PROTEIN