Mechanistic insights of substrate transport and inhibitor binding revealed by high-resolution structures of human norepinephrine transporter
Ailong Song, Xudong Wu
Abstract
Norepinephrine (NE), also known as noradrenaline, is an important neurotransmitter that plays crucial roles in the central nervous system, including the regulation of mood, memory, and alertness. It also functions as a key hormone in the whole body. In the brain, NE transporter (NET, encoded by the SLC6A2 gene), a Na + /Cl – -dependent transporter, reuptakes released NE at neuron synapses, thus maintaining NE homeostasis. Due to the important functions of NET, many drugs targeting NET have been developed to treat various neurological disorders. 1 Despite previous efforts using NET surrogate to gain insights into the transport mechanism, 2 the specific recognition of NE and the mechanistic details of the transport process remain elusive. Moreover, the binding modes of several FDA-approved NET-selective inhibitors require further investigations to provide a solid model for future structure-based drug discovery.