2013年11月11日訊 /生物谷BIOON/--近日,俄勒岡健康與科學大學Vollum研究所在最新一期Nature上發表論文,研究成果給科學家們了解有關神經細胞之間如何相互溝通提供了新的見解。研究詳細地闡述了一種控制神經細胞之間通信的蛋白質的結構。
新研究讓科學家更好地了解抗抑鬱藥在人類大腦中的工作方式,有助於開發副作用很小或無副作用的抗抑鬱藥。研究側重關注多巴胺轉運蛋白的結構,多巴胺轉運蛋白有助於調節大腦中多巴胺水平。多巴胺是人體中樞神經系統必不可少的神經遞質,在一系列神經系統疾病,包括帕金森氏症,藥物成癮,抑鬱症和精神分裂症中可見多巴胺水平異常。
與多巴胺一起,神經遞質去甲腎上腺素和5-羥色胺被相關轉運蛋白運輸,Gouaux實驗室詳細揭示了多巴胺轉運蛋白結構,更好地揭示了抗抑鬱藥如何作用於轉運蛋白,從而發揮治療功效。
Gouaux說:更詳細的轉運蛋白結構視圖可以幫助科學家和製藥公司開發新的藥物,通過儘可能學習轉運蛋白的結構及其與抗抑鬱藥之間的相互作用,我們已經奠定了設計功效更好、有害副作用更少的治療新藥物分子的基礎。
而Gouaux等人最新的有關多巴胺轉運蛋白的研究論文也很重要,因為研究使用果蠅作為模型,果蠅多巴胺轉運蛋白分子更類似於人類。新文章中還涉及用修飾過的胺基酸轉運蛋白模擬哺乳動物神經遞質轉運蛋白,闡明抗抑鬱藥的作用機制。
Gouaux說:研究告訴我們很多關於這些轉運蛋白是如何工作,以及這些轉運蛋白如何與抗抑鬱藥分子相互作用的信息。研究具有重要意義,不只幫助理解抗抑鬱藥的機制,同時也有助探究其他精神疾病和神經系統疾病治療藥物的作用機制。(生物谷Bioon.com)
X-ray structure of dopamine transporter elucidates antidepressant mechanism.
Aravind Penmatsa, Kevin H. Wang, Eric Gouaux
Antidepressants targeting Na+/Cl-coupled neurotransmitter uptake define a key therapeutic strategy to treat clinical depression and neuropathic pain. However, identifying the molecular interactions that underlie the pharmacological activity of these transport inhibitors, and thus the mechanism by which the inhibitors lead to increased synaptic neurotransmitter levels, has proven elusive. Here we present the crystal structure of the Drosophila melanogaster dopamine transporter at 3.0 resolution bound to the tricyclic antidepressant nortriptyline. The transporter is locked in an outward-open conformation with nortriptyline wedged between transmembrane helices 1, 3, 6 and 8, blocking the transporter from binding substrate and from isomerizing to an inward-facing conformation. Although the overall structure of the dopamine transporter is similar to that of its prokaryotic relative LeuT, there are multiple distinctions, including a kink in transmembrane helix 12 halfway across the membrane bilayer, a latch-like carboxy-terminal helix that caps the cytoplasmic gate, and a cholesterol molecule wedged within a groove formed by transmembrane helices 1a, 5 and 7. Taken together, the dopamine transporter structure reveals the molecular basis for antidepressant action on sodium-coupled neurotransmitter symporters and elucidates critical elements of eukaryotic transporter structure and modulation by lipids, thus expanding our understanding of the mechanism and regulation of neurotransmitter uptake at chemical synapses.
doi:10.1038/nature12648
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Structural basis for action by diverse antidepressants on biogenic amine transporters.
Hui Wang, April Goehring, Kevin H. Wang, Aravind Penmatsa, Ryan Ressler, Eric Gouaux
The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin–noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)1, 2. Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homologue of BATs and has proven to be a valuable paradigm for understanding relationships between their structure and function3. However, because only approximately 25% of the amino acid sequence of LeuT is in common with that of BATs, and as LeuT is a promiscuous amino acid transporter4, it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT5, 6, 7 and act as non-competitive inhibitors of transport5. By contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket8, 9, 10, 11, 12, 13, 14, 15, 16. Here we engineered LeuT to harbour human BAT-like pharmacology by mutating key residues around the primary binding pocket. The final LeuBAT mutant binds the SSRI sertraline with a binding constant of 18?nM and displays high-affinity binding to a range of SSRIs, SNRIs and a TCA. We determined 12 crystal structures of LeuBAT in complex with four classes of antidepressants. The chemically diverse inhibitors have a remarkably similar mode of binding in which they straddle transmembrane helix (TM) 3, wedge between TM3/TM8 and TM1/TM6, and lock the transporter in a sodium- and chloride-bound outward-facing open conformation. Together, these studies define common and simple principles for the action of SSRIs, SNRIs and TCAs on BATs.