Structural insights into substrate transport and drug inhibition of the human vesicular monoamine transporter 2 ( VMAT2 )

This is the authors' abstract. We don't add key points for this paper.

Vesicular monoamine transporter 2 (VMAT2) is a proton-monoamine antiporter that is widely expressed in central and peripheral neurons and plays a crucial role in loading monoamine neurotransmitters into secretory vesicles. Dysfunction of VMAT2 causes many neuropsychiatric disorders, such as depression and Parkinson's disease. Consequently, VMAT2 is a valid and important therapeutic target. Reserpine alleviates symptoms of hypertension via potent inhibition of VMAT2. Tetrabenazine selectively inhibits VMAT2 and has been used for the management of chorea, including Huntington's disease. Decades of extensive studies have defined the substrate specificity and transport kinetics of VMAT2. However, the structure and precise mechanisms of monoamine recognition and drug inhibition in VMAT2 remain unknown. Recently, we determined an ensemble of high-resolution cryo-EM structures of human VMAT2 in three distinct states bound to multiple substrates and inhibitors. These results lay a structural foundation for a comprehensive understanding of substrate recognition and transport, drug inhibition, and proton coupling in VMAT2 and shed light on future therapeutic development.