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Structural Models of Human Norepinephrine Transporter Ensemble Reveal the Allosteric Sites and Ligand-Binding Mechanism.
Luo, Ding; Zhang, Yang; Li, Yinghong; Liu, Zerong; Wu, Haibo; Xue, Weiwei.
Afiliación
  • Luo D; Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
  • Zhang Y; School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China.
  • Li Y; Chongqing Key Laboratory of Big Data for Bio Intelligence, Chongqing University of Posts and Telecommunications, Chongqing 400065, China.
  • Liu Z; Central Nervous System Drug Key Laboratory of Sichuan Province, Sichuan Credit Pharmaceutical Co., Ltd., Luzhou 646000, China.
  • Wu H; School of Life Sciences, Chongqing University, Chongqing 401331, China.
  • Xue W; Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
J Phys Chem B ; 128(36): 8651-8661, 2024 Sep 12.
Article en En | MEDLINE | ID: mdl-39207306
ABSTRACT
The norepinephrine transporter (NET) plays a pivotal role in recycling norepinephrine (NE) from the synaptic cleft. However, the structures referring to the conformational heterogeneity of NET during the transport cycle remain poorly understood. Here, three structural models of NE bound to the orthosteric site of NET in outward-open (OOholo), outward-occluded (OCholo), and inward-open (IOholo) conformations were first obtained using the multistate structures of serotonin transporter as templates and further characterized through Gaussian-accelerated molecular dynamics and free energy reweighting. Analysis of the structures revealed eight potential allosteric sites on the functional-specific states of NET. One of the pharmacologically relevant pockets located at the extracellular vestibule was further verified by simulating the binding behaviors of a clinical trial drug χ-MrIA that is allosterically regulating NET. These structural and energetic insights into NET advanced our understanding of NE reuptake and paved the way for discovering novel molecules targeting the allosteric sites.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sitio Alostérico / Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática / Simulación de Dinámica Molecular Límite: Humans Idioma: En Revista: J Phys Chem B Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sitio Alostérico / Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática / Simulación de Dinámica Molecular Límite: Humans Idioma: En Revista: J Phys Chem B Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos