Wei Feiwen, Liu Huihui, Zhang Wei, Wang Jufang, Zhang Yanqing
Shanghai Fifth People's Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Arieh Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China.
Nat Commun. 2025 Jan 2;16(1):323. doi: 10.1038/s41467-024-55361-0.
Vesicular monoamine transporter 2 (VMAT2) is crucial for packaging monoamine neurotransmitters into synaptic vesicles, with their dysregulation linked to schizophrenia, mood disorders, and Parkinson's disease. Tetrabenazine (TBZ) and valbenazine (VBZ), both FDA-approved VMAT2 inhibitors, are employed to treat chorea and tardive dyskinesia (TD). Our study presents the structures of VMAT2 bound to substrates serotonin (5-HT) and dopamine (DA), as well as the inhibitors TBZ and VBZ. Utilizing cryo-electron microscopy (cryo-EM), mutagenesis functional assays, and molecular dynamics (MD) simulations, we elucidate the mechanisms of substrate transport and drug inhibition. Our MD simulations indicate potential binding poses of substrate (5-HT) in both cytosol-facing and lumen-facing states, emphasizing the significance of protonation of key acidic residues for substrate release. We demonstrate that TBZ locks VMAT2 in a lumen-facing occluded state, while VBZ stabilizes it in a lumen-facing conformation. These insights enhance our understanding of VMAT2 function and provide valuable insights for the development of novel therapeutic strategies for psychiatric disorders.
囊泡单胺转运体2（VMAT2）对于将单胺类神经递质包装到突触小泡中至关重要，其功能失调与精神分裂症、情绪障碍和帕金森病有关。丁苯那嗪（TBZ）和缬苯那嗪（VBZ）均为美国食品药品监督管理局（FDA）批准的VMAT2抑制剂，用于治疗舞蹈症和迟发性运动障碍（TD）。我们的研究展示了与底物血清素（5-HT）、多巴胺（DA）以及抑制剂TBZ和VBZ结合的VMAT2的结构。利用冷冻电子显微镜（cryo-EM）、诱变功能测定和分子动力学（MD）模拟，我们阐明了底物转运和药物抑制的机制。我们的MD模拟表明了底物（5-HT）在面向胞质溶胶状态和面向内腔状态下的潜在结合姿势，强调了关键酸性残基质子化对于底物释放的重要性。我们证明TBZ将VMAT2锁定在面向内腔的封闭状态，而VBZ使其稳定在面向内腔的构象。这些见解加深了我们对VMAT2功能的理解，并为精神疾病新型治疗策略的开发提供了有价值的见解。
